ADVERSE REACTIONS SECTION.

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 (5.2)] Infusion-Related Reactions [see Warnings and Precautions (5.5)] Serious Meningococcal Infections [see Warnings and Precautions (5.1)] Other Infections [see Warnings and Precautions (5.2)] Infusion-Related Reactions [see Warnings and Precautions (5.5)] 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).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.. 6.1Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 PNHThe data described below reflect exposure of 441 adult patients with PNH in Phase studies who received ULTOMIRIS (n 222) or eculizumab (n 219) at the recommended dosing regimens with median treatment duration of months for ULTOMIRIS and months for eculizumab. The most frequent adverse reactions (>=10%) with ULTOMIRIS were upper respiratory tract infection and headache. Table describes adverse reactions that occurred at 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 patient treated with ULTOMIRIS.One fatal case of sepsis was identified in patient treated with ULTOMIRIS.Table 6: Adverse Reactions Reported in 5% or More of ULTOMIRIS-Treated Patients in Complement Inhibitor Naive and Eculizumab-Experienced Adult Patients with PNHBody System Adverse ReactionNumber of PatientsULTOMIRIS (N=222) (%)Eculizumab (N=219) (%)Gastrointestinal disorders Diarrhea19 (9)12 (5) Nausea19 (9)19 (9) Abdominal pain13 (6)16 (7)General Disorders and Administration Site Conditions Pyrexia15 (7)18 (8)Infections and Infestations Upper respiratory tract infectionGrouped 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 extremity14 (6)11 (5) Arthralgia11 (5)12 (5)Nervous System Disorders Headache71 (32)57 (26) Dizziness12 (5)14 (6)Clinically relevant adverse reactions in 1% of patients include infusion-related reactions.. Pediatric population with PNHIn pediatric patients with PNH (aged to 17 years old) included in the pediatric PNH Phase 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 describes the adverse reactions that occurred at rate of 10% or more among pediatric patients treated with ULTOMIRIS in Study ALXN1210-PNH-304.Table 7: Adverse Reactions Reported in 10% or More of ULTOMIRIS-Treated Pediatric Patients with PNH in Study ALXN1210-PNH-304Body System Adverse ReactionTreatment Naive(N=5)Eculizumab Experienced(N=8)Total(N=13)n (%)n (%)n (%)Blood and lymphatic system disorders AnemiaGrouped term includes: anemia and iron deficiency anemia (20)2 (25)3 (23)Gastrointestinal disorders Abdominal pain0 (0)3 (38)3 (23) Constipation0 (0)2 (25)2 (15)General disorders and administration site conditions Pyrexia1 (20)1 (13)2 (15)Infections and infestations Upper Respiratory tract infectionGrouped term includes: nasopharyngitis, upper respiratory tract infection, oropharyngeal pain and viral upper respiratory tract infection (20)6 (75)7 (54)Musculoskeletal and connective tissue disorders Pain in extremity0 (0)2 (25)2 (15)Nervous system disorders Headache1 (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. Tables 8, and 10 describe adverse reactions that occurred at 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 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 two patients and intracranial hemorrhage in one patient. The fourth patient, who was excluded from the trial after diagnosis of STEC-HUS, died due to pretreatment cerebral arterial thrombosis.Table 8: Adverse Reactions Reported in >=10% of ULTOMIRIS-Treated Patients with aHUS in Study ALXN1210-aHUS-311Body System Adverse ReactionALXN1210-aHUS-311 (N=58)All Grades: Graded per CTCAE v5.0. (n=53) (%)>= Grade (n=14) (%)Blood and lymphatic system disorders Anemia8 (14)0 (0)Gastrointestinal disorders Diarrhea18 (31)2 (3) Nausea15 (26)2 (3) Vomiting15 (26)2 (3) Constipation8 (14)1 (2) Abdominal pain7 (12)1 (2)General disorders and administration site conditions Pyrexia11 (19)1 (2) Edema peripheral10 (17)0 (0) Fatigue8 (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 infection10 (17)5 (9) Gastrointestinal infection: Grouped term includes gastroenteritis, gastrointestinal infection, enterocolitis infectious,infectious colitis, and enterocolitis. (14)2 (3)Metabolism and nutrition disorders Hypokalemia6 (10)1 (2)Musculoskeletal and connective tissue disorders Arthralgia13 (22)0 (0) Back pain7 (12)1 (2) Muscle spasms6 (10)0 (0) Pain in extremity6 (10)0 (0)Nervous system disorders Headache23 (40)1 (2)Psychiatric disorders Anxiety8 (14)1 (2)Respiratory, thoracic and mediastinal disorders Cough10 (17)0 (0) Dyspnea10 (17)1 (2)Skin and subcutaneous tissue disorders Alopecia6 (10)0 (0) Dry skin6 (10)0 (0)Vascular disorders Hypertension14 (24)7 (12)Clinically relevant adverse reactions include viral tonsilitis (in <10% of patients) and infusion-related reactions (in 3% of patients).Table 9: Adverse Reactions Reported in >=10% of ULTOMIRIS-Treated Patients with aHUS in Study ALXN1210-aHUS-312Body System Adverse ReactionALXN1210-aHUS-312 (N=16)All Grades: Graded per CTCAE v5.0. (n=16) (%)>= Grade (n=6) (%)Blood and lymphatic system disorders Anemia2 (13)1 (6) Lymphadenopathy2 (13)0 (0)Gastrointestinal disorders Diarrhea6 (38)0 (0) Constipation4 (25)0 (0) Vomiting4 (25)1 (6) Abdominal pain3 (19)0 (0) Nausea2 (13)0 (0)General disorders and administration site conditions Pyrexia8 (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. (44)1 (6) Gastroenteritis viral2 (13)2 (13) Pneumonia2 (13)1 (6) Tonsillitis2 (13)0 (0)Injury, poisoning and procedural complications Contusion3 (19)0 (0)Investigations Vitamin decreased3 (19)0 (0)Metabolism and nutrition disorders Decreased appetite2 (13)0 (0) Iron deficiency2 (13)0 (0)Musculoskeletal and connective tissue disorders Myalgia3 (19)0 (0) Pain in extremity2 (13)0 (0)Nervous system disorders Headache5 (31)0 (0)Respiratory, thoracic and mediastinal disorders Cough3 (19)0 (0) Dyspnea2 (13)0 (0)Skin and subcutaneous tissue disorders Rash3 (19)0 (0)Vascular disorders Hypertension4 (25)1 (6) Hypotension2 (13)0 (0)Clinically relevant adverse reactions in <10% of patients include viral infection.Table 10: Adverse Reactions Reported in >=10% of ULTOMIRIS-Treated Patients from Birth to 16 Years of Age with aHUS in Study ALXN1210-aHUS-312Body System Adverse ReactionALXN1210-aHUS-312Age to <2 (N=2)Age to <12 (N=12)Age 12 to 16 (N=1)Total (N=15)n (%)n (%)n (%)n (%)Blood and lymphatic system disorders Lymphadenopathy0 (0)2 (17)0 (0)2 (13)Gastrointestinal disorders Diarrhea1 (50)3 (25)1 (100)5 (33) Constipation0 (0)4 (33)0 (0)4 (27) Vomiting0 (0)3 (25)0 (0)3 (20) Abdominal pain0 (0)2 (17)0 (0)2 (13)General disorders and administration site conditions Pyrexia1 (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 (50)6 (50)0 (0)7 (47) Gastroenteritis viral0 (0)2 (17)0 (0)2 (13) Tonsillitis1 (50)1 (8)0 (0)2 (13)Injury, poisoning and procedural complications Contusion0 (0)2 (17)0 (0)2 (13)Investigations Vitamin decreased0 (0)2 (17)1 (100)3 (20)Metabolism and nutrition disorders Decreased appetite1 (50)1 (8)0 (0)2 (13) Iron deficiency0 (0)2 (17)0 (0)2 (13)Musculoskeletal and connective tissue disorders Myalgia1 (50)1 (8)0 (0)2 (13) Pain in extremity0 (0)2 (17)0 (0)2 (13)Nervous system disorders Headache0 (0)4 (33)0 (0)4 (27)Respiratory, thoracic and mediastinal disorders Cough0 (0)3 (25)0 (0)3 (20) Dyspnea1 (50)1 (8)0 (0)2 (13)Skin and subcutaneous tissue disorders Rash1 (50)2 (17)0 (0)3 (20)Vascular disorders Hypertension1 (50)3 (25)0 (0)4 (27) Hypotension0 (0)2 (17)0 (0)2 (13)Clinically relevant adverse reactions in <10% of patients include viral infection.. 6.2 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibodies) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other ravulizumab-cwvz products may be misleading.The immunogenicity of ravulizumab-cwvz has been evaluated using an enzyme-linked immunosorbent assay (ELISA) for the detection of binding anti-ravulizumab-cwvz antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies.In clinical studies, treatment-emergent antibodies to ravulizumab-cwvz were detected in of 219 (0.5%) patients with PNH and of 71 (1.4%) patients with aHUS. In these patients, no apparent correlation of antibody development to altered pharmacokinetic profile, clinical response, or adverse events was observed. However, the assay used to measure anti-drug antibodies (ADA) is subject to interference by serum ravulizumab-cwvz, possibly resulting in an underestimation of the incidence of antibody formation. Due to the limitation of the assay conditions, the potential clinical impact of antibodies to ravulizumab-cwvz is not known.. 6.3 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of ULTOMIRIS. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to ULTOMIRIS exposure.Serious Adverse Reaction: Anaphylaxis.

BOXED WARNING SECTION.

WARNING: SERIOUS MENINGOCOCCAL INFECTIONS. Life-threatening meningococcal infections/sepsis have occurred in patients treated with ULTOMIRIS. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early [see Warnings and Precautions (5.1)].Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies.Immunize patients with meningococcal vaccines at least weeks prior to administering the first dose of ULTOMIRIS, unless the risks of delaying ULTOMIRIS therapy outweigh the risk of developing meningococcal infection. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of meningococcal infection.Vaccination reduces, but does not eliminate, the risk of meningococcal infections. Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected.ULTOMIRIS is available only through restricted program under Risk Evaluation and Mitigation Strategy (REMS). Under the ULTOMIRIS REMS, prescribers must enroll in the program [see Warnings and Precautions (5.1)]. Enrollment in the ULTOMIRIS REMS program and additional information are available by telephone: 1-888-765-4747 or at www.ultomirisrems.com.. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies.. Immunize patients with meningococcal vaccines at least weeks prior to administering the first dose of ULTOMIRIS, unless the risks of delaying ULTOMIRIS therapy outweigh the risk of developing meningococcal infection. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of meningococcal infection.. Vaccination reduces, but does not eliminate, the risk of meningococcal infections. Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected.. WARNING: SERIOUS MENINGOCOCCAL INFECTIONSSee full prescribing information for complete boxed warningLife-threatening meningococcal infections/sepsis have occurred in patients treated with ULTOMIRIS and may become rapidly life-threatening or fatal if not recognized and treated early (5.1).Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies (5.1).Immunize patients with meningococcal vaccines at least weeks prior to administering the first dose of ULTOMIRIS, unless the risks of delaying ULTOMIRIS therapy outweigh the risks of developing meningococcal infection. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of meningococcal infection.Vaccination reduces, but does not eliminate, the risk of meningococcal infection. Monitor patients for early signs of meningococcal infections, and evaluate immediately if infection is suspected.ULTOMIRIS is available only through restricted program under Risk Evaluation and Mitigation Strategy (REMS). Under the ULTOMIRIS REMS, prescribers must enroll in the program (5.1).. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies (5.1).. Immunize patients with meningococcal vaccines at least weeks prior to administering the first dose of ULTOMIRIS, unless the risks of delaying ULTOMIRIS therapy outweigh the risks of developing meningococcal infection. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of meningococcal infection.. Vaccination reduces, but does not eliminate, the risk of meningococcal infection. Monitor patients for early signs of meningococcal infections, and evaluate immediately if infection is suspected.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term animal carcinogenicity studies of ravulizumab-cwvz have not been conducted.Genotoxicity studies have not been conducted with ravulizumab-cwvz.Effects of ravulizumab-cwvz upon fertility have not been studied in animals. Intravenous injections of male and female mice with murine anti-C5 antibody at up to 0.8-2.2 times the equivalent of the clinical dose of ULTOMIRIS had no adverse effects on mating or fertility.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. Ravulizumab-cwvz is 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 terminal complement complex [C5b-9]) and preventing the generation of the terminal complement complex C5b9. ULTOMIRIS inhibits terminal complement-mediated intravascular hemolysis in patients with PNH and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS.. 12.2 Pharmacodynamics. Complete inhibition of serum free C5 (concentration of less than 0.5 mcg/mL) was observed by the end of the first ULTOMIRIS infusion and sustained throughout the entire 26-week treatment period in both adult and pediatric patients with PNH and in the majority (93%) of adult and pediatric patients with aHUS.The extent and duration of the pharmacodynamic response in patients with PNH and aHUS were exposure-dependent for ULTOMIRIS. Free C5 levels of <0.5 mcg/mL were correlated with maximal intravascular hemolysis control and complete terminal complement inhibition in patients with PNH.Complete terminal complement inhibition following initiation of ULTOMIRIS treatment led to normalization of serum LDH by week in complement-inhibitor naive patients with PNH, and maintained LDH normalization in patients previously treated with eculizumab with PNH [see Clinical Studies (14)].. 12.3 Pharmacokinetics. Ravulizumab-cwvz pharmacokinetics increase proportionally over dose range of 200 to 5400 mg. Ravulizumab-cwvz Cmax and Ctrough parameters are presented in Table 11 and Table 12.Table 11: Mean (%CV) Pharmacokinetic Parameters of ULTOMIRIS in Patients with PNH who are Complement Inhibitor-Naive and Patients Previously Treated with EculizumabPediatric PatientsAdult PatientsALXN1210-PNH-304ALXN1210-PNH-301ALXN1210-PNH-302NComplement Inhibitor- NaiveNPreviously Treated with EculizumabNComplement Inhibitor- NaiveNPreviously Treated with EculizumabLD Loading Dose; MD Maintenance DoseLD4733 (14.5)8885 (19.3)125771 (21.5)95843 (24.1)Cmax (mcg/mL)MD41490 (26.7)81705 (9.7)1241,379 (20.0)951,386 (19.4)Ctrough (mcg/mL)LD4368 (14.7)8452 (15.1)125391 (35.0)96405 (29.9)MD4495 (21.3)8566 (12.2)124473 (33.4)95501 (28.6)Table 12: Mean (%CV) Pharmacokinetic Parameters of ULTOMIRIS in Patients with aHUSPediatric Patients (ALXN1210-aHUS-312)Adult Patients (ALXN1210-aHUS-311)N< 20 kg MD Q4WN>= 20 to 40 kg MD Q8WN>= 40 kg MD Q8WLD Loading Dose; MD Maintenance Dose; Q4W Every Weeks; Q8W Every WeeksCmax (mcg/mL)LD8656 (38.1)4600 (17.3)52754 (35.2)MD71,467 (37.8)61,863 (15.3)461,458 (17.6)Ctrough (mcg/mL)LD9241 (52.1)5186 (16.5)55313 (33.9)MD7683 (46.1)6549 (34.1)46507 (42.5). DistributionThe mean (%CV) volume of distribution at steady state was 5.30 (17.9) and 5.22 (35.4) in patients with PNH and aHUS, respectively.. EliminationThe mean (%CV) terminal elimination half-life of ravulizumab-cwvz was 49.6 (18.3) days and 51.8 (31.3) days in patients with PNH and aHUS, respectively. The mean (%CV) clearance of ravulizumab-cwvz was 0.08 (28.1) L/day and 0.08 (53.3) L/day in patients with PNH and aHUS, respectively.. Specific PopulationsNo 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 clinically significant covariate on the pharmacokinetics of ravulizumab-cwvz.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Paroxysmal Nocturnal Hemoglobinuria (PNH). The safety and efficacy of ULTOMIRIS in adult patients with PNH was assessed in two open-label, randomized, active-controlled, non-inferiority Phase studies: PNH Study 301 and PNH Study 302. Study 301 enrolled patients with PNH who were complement inhibitor naive and had active hemolysis. Study 302 enrolled patients with PNH who were clinically stable after having been treated with eculizumab for at least the past months. The safety and efficacy of ULTOMIRIS in pediatric patients with PNH was assessed in PNH Study 304, open-label, Phase study conducted in eculizumab-experienced and complement inhibitor treatment naive pediatric patients with PNH.In both adult studies, ULTOMIRIS was dosed intravenously in accordance with the weight-based dosing described in Section 2.2 (4 infusions of ULTOMIRIS over 26 weeks) above. Eculizumab was administered on Days 1, 8, 15, and 22, followed by maintenance treatment with 900 mg of eculizumab on Day 29 and every weeks (q2w) thereafter for total of 26 weeks of treatment, according to the approved dosing regimen of eculizumab which was the standard-of-care for PNH at the time of the studies.Patients were vaccinated against meningococcal infection prior to or at the time of initiating treatment with ULTOMIRIS or eculizumab, or received prophylactic treatment with appropriate antibiotics until weeks after vaccination. Prophylactic treatment with appropriate antibiotics beyond weeks after vaccination was at the discretion of the provider.. Study in Complement-Inhibitor Naive Adult Patients with PNHThe Complement-Inhibitor Naive Study [ALXN1210-PNH-301; NCT02946463] was 26-week, multicenter, open-label, randomized, active-controlled, non-inferiority Phase study conducted in 246 patients naive to complement inhibitor treatment prior to study entry.Patients with PNH with flow cytometric confirmation of at least 5% PNH cells were randomized 1:1 to either ULTOMIRIS or eculizumab. The mean total PNH granulocyte clone size was 85%, the mean total PNH monocyte clone size was 88%, and the mean total PNH RBC clone size was 39%. Ninety-eight percent of patients had documented PNH-associated condition diagnosed prior to enrollment on the trial: anemia (85%), hemoglobinuria (63%), history of aplastic anemia (32%), history of renal failure (12%), myelodysplastic syndrome (5%), pregnancy complications (3%), and other (16%). Major baseline characteristics were balanced between treatment groups. Table 13 provides the baseline characteristics for the patients enrolled in the complement-inhibitor naive study.Table 13: Baseline Characteristics in the Complement-Inhibitor Naive StudyParameterStatisticsULTOMIRIS (N=125)Eculizumab (N=121)Age (years) at first infusion in studyMean (SD)44.8 (15.2)46.2 (16.2)Min, max18, 8318, 86Sex Malen (%)65 (52.0)69 (57.0)Racen (%) Asian72 (57.6)57 (47.1) White43 (34.4)51 (42.1) Black or African American2 1.6)4 3.3) American Indian or Alaska Native1 0.8)1 0.8) Other4 3.2)4 3.3) Not reported3 2.4)4 3.3)Pre-treatment LDH levels (U/L)Median1513.51445.0Min, max(378.0, 3759.5)(423.5, 3139.5)Units of pRBC/whole blood transfused within 12 months prior to first doseMedianMin, max6.0(1, 44)6.0(1, 32)Antithrombotic agents used within 28 days prior to first dosen (%)22 (17.6)22 (18.2)Patients with history of MAVE MAVE major adverse vascular event (%)17 (13.6)25 (20.7)Patients with history of thrombosisn (%)17 (13.6)20 (16.5)Patients with concomitant anticoagulant treatmentn (%)23 (18.4)28 (23.1)Efficacy was established based upon transfusion avoidance and hemolysis as directly measured by normalization of LDH levels. Transfusion avoidance was defined as patients who did not receive transfusion and did not meet the protocol specified guidelines for transfusion from baseline up to Day 183. Supportive efficacy data included the percent change from baseline in LDH levels, the proportion of patients with breakthrough hemolysis defined as at least one new or worsening symptom or sign of intravascular hemolysis in the presence of elevated LDH >= x ULN, after prior LDH reduction to 1.5 ULN on therapy and the proportion of patients with stabilized hemoglobin.Non-inferiority of ULTOMIRIS to eculizumab was demonstrated across endpoints in the complement inhibitor naive treatment population described in Table 14 below.Table 14: Efficacy Results in the Complement-Inhibitor Naive StudyULTOMIRIS (N=125)Eculizumab (N=121)Statistic for ComparisonTreatment Effect (95% CI)Note: LDH lactate dehydrogenase; CI confidence intervalFor the transfusion avoidance endpoint, treatment differences (95% CIs) are based on estimated differences in percent with 95% CI. For the lactate dehydrogenase normalization endpoint, the adjusted prevalence within each treatment is displayed.Transfusion avoidance rate73.6%66.1%Difference in rate6.8 (-4.66, 18.14)LDH normalization53.6%49.4%Odds ratio1.19 (0.80, 1.77)LDH percent change-76.84%-76.02%Difference in change from baseline-0.83 (-5.21, 3.56)Breakthrough hemolysis4.0%10.7%Difference in rate-6.7 (-14.21, 0.18)Hemoglobin stabilization68.0%64.5%Difference in rate2.9 (-8.80, 14.64)There was no observable difference in fatigue between ULTOMIRIS and eculizumab after 26 weeks of treatment compared to baseline as measured by the FACIT-fatigue instrument. Patient-reported fatigue may be an under-or over-estimation, because patients were not blinded to treatment assignment.. Study in Eculizumab-Experienced Adult Patients with PNHThe study in eculizumab-experienced patients [ALXN1210-PNH-302; NCT03056040] was 26-week, multicenter, open-label, randomized, active-controlled, non-inferiority Phase study conducted in 195 patients with PNH who were clinically stable after having been treated with eculizumab for at least the past months.Patients who demonstrated clinically stable disease after being treated with eculizumab for at least the prior months were randomized 1:1 to either continue eculizumab or to switch to ULTOMIRIS. The mean total PNH granulocyte clone size was 83%, the mean total PNH monocyte clone size was 86%, and the mean total PNH RBC clone size was 60%. Ninety five percent of patients had documented PNH-associated condition diagnosed prior to enrollment in the trial: anemia (67%), hematuria or hemoglobinuria (49%), history of aplastic anemia (37%), history of renal failure (9%), myelodysplastic syndrome (5%), pregnancy complication (7%), and other (14%). Major baseline characteristics were balanced between the two treatment groups. Table 15 provides the baseline characteristics for the patients enrolled in the eclulizumab-experienced study.Table 15:Baseline Characteristics in Eculizumab-Experienced Adult Patients with PNHParameterStatisticsULTOMIRIS (N=97)Eculizumab (N=98)Age (years) at first infusion in studyMean (SD)46.6 (14.41)48.8 (13.97)Min, max18, 7923, 77Racen (%) White50 (51.5)61 (62.2) Asian23 (23.7)19 (19.4) Black or African American5 (5.2)3 (3.1) Other2 (2.1)1 (1.0) Not reported13 (13.4)13 (13.3) Unknown3 (3.1)1 (1.0) Multiple1 (1.0)0Sexn (%) Male50 (51.5)48 (49.0)Pre-treatment LDH levels (U/L)Median224.0234.0Min, max135.0, 383.5100.0, 365.5Units of pRBC/whole blood transfused within 12 months prior to first doseMedian4.02.5Min, max(1, 32)(2, 15)Antithrombotic agents used within 28 days prior to first dosen (%)20 (20.6)13 (13.3)Patients with history of MAVEMAVE major adverse vascular event (%)28 (28.9)22 (22.4)Patients with history of thrombosisn (%)27 (27.8)21 (21.4)Patients with concomitant anticoagulant treatment (%)22 (22.7)16 (16.3)Efficacy was established based on hemolysis as measured by LDH percent change from baseline to Day 183 and supportive efficacy data was transfusion avoidance, proportion of patients with stabilized hemoglobin, and the proportion of patients with breakthrough hemolysis through Day 183.Non-inferiority of ULTOMIRIS to eculizumab was demonstrated across endpoints in the patients with PNH previously treated with eculizumab described in Table 16 below.Table 16: Efficacy Results in the Eculizumab-Experienced Adult Patients with PNH Eculizumab-Experienced StudyULTOMIRIS = 97Eculizumab = 98Statistic for ComparisonTreatment Effect (95% CI)Note: CI confidence intervalLDH percent change-0.82%8.4%Difference in change from baseline9.2 (-0.42, 18.8)Breakthrough hemolysis0%5.1%Difference in rate5.1 (-8.9, 19.0)Transfusion avoidance87.6 %82.7%Difference in rate5.5 (-4.3, 15.7)Hemoglobin stabilization76.3%75.5%Difference in rate1.4 (-10.4, 13.3)There was no observable difference in fatigue between ULTOMIRIS and eculizumab after 26 weeks of treatment compared to baseline as measured by the FACIT-fatigue instrument. Patient-reported fatigue may be an under-or over-estimation, because patients were not blinded to treatment assignment.. Study in Eculizumab-Experienced and Complement-Inhibitor Naive Pediatric Patients with PNHThe pediatric study, ALXN1210-PNH-304, was multi-center, open-label Phase study conducted in eculizumab-experienced and complement inhibitor treatment-naive pediatric patients with PNH. total of 13 pediatric patients with PNH completed ULTOMIRIS treatment during the Primary Evaluation Period (26 weeks). Five of the 13 patients had never been treated with complement inhibitors and patients were treated with eculizumab. Eleven of the thirteen patients were between 12 and 17 years of age at first infusion, with patients under 12 years old (11 and years old). Table 17 presents the baseline characteristics of the pediatric patients enrolled in Study ALXN1210-PNH-304.Table 17:Baseline Characteristics for Pediatric Patients with PNHVariableComplement Inhibitor Treatment-naive Patients (N 5)Eculizumab-Experienced Patients (N 8)All Patients(N 13)Note: Percentages were based on the total number of patients in each cohort, or overall.kg kilogram; max maximum; min minimum; SD standard deviation.Sex, (%) Male4 (80.0)1 (12.5)5 (38.5) Female1 (20.0)7 (87.5)8 (61.5)Age at first infusion (years) Mean (SD)14.4 (2.2)14.4 (3.1)14.4 (2.7) Median (min, max)15.0 (11, 17)15.0 (9, 17)15.0 (9, 17)Age at first infusion (years) category, (%) 12 years1 (20.0)1 (12.5)2 (15.4) >= 12 years4 (80.0)7 (87.5)11 (84.6)Baseline weight (kg) Mean (SD)56.3 (11.6)56.3 (12.2)56.3 (11.5) Median (min, max)55.6 (39.5, 72.0)55.5 (36.7, 69.0)55.6 (36.7, 72.0)Baseline weight (kg) category, (%) >= 30 to 40 kg1 (20.0)1 (12.5)2 (15.4) >= 40 to 60 kg3 (60.0)4 (50.0)7 (53.8) >= 60 to 100 kg1 (20.0)3 (37.5)4 (30.8)Units of pRBC/whole blood transfused within 12 months prior to first dose- Median (min, max)7.0 (3, 11)2.0 (2, 2)Pre-treatment LDH levels (U/L)- Median (min, max)588.5 (444, 2269.7)251.5 (140.5, 487)Based on body weight, patients received loading dose of ULTOMIRIS on Day 1, followed by maintenance treatment on Day 15 and once every weeks (q8w) thereafter for patients weighing >= 20 kg, or once every weeks (q4w) for patients weighing 20 kg. For patients who entered the study on eculizumab therapy, Day of study treatment was planned to occur weeks from the patients last dose of SOLIRIS.The weight-based dose regimen of ravulizumab-cwvz provided inhibition of terminal complement in all patients throughout the entire 26-week treatment period regardless of prior experience with eculizumab. Following initiation of ravulizumab-cwvz treatment, steady-state therapeutic serum concentrations of ravulizumab-cwvz were achieved after the first dose and maintained throughout the primary evaluation period in both cohorts. Three of complement inhibitor treatment-naive patients and out of eculizumab-experienced patients achieved hemoglobin stabilization by Week 26, respectively. Transfusion avoidance was reached for 11 out of 13 of patients during the 26-week Primary Evaluation Period. One patient experienced breakthrough hemolysis during the extension period. Table 18 presents secondary efficacy outcomes for the primary evaluation period.Table 18: Efficacy Outcomes from the 26-Week Primary Evaluation Period of Pediatric Patient Study in PNH (ALXN1210-PNH-304)End PointTreatment Naive(N 5)Eculizumab Experienced (N 8)LDH lactate dehydrogenaseLDH- Percent Change from Baseline (%)95% CIs for the mean obtained from t-distribution were presented. -47.9 (-113.4, 17.5)4.7 (-36.7, 46.0)Transfusion Avoidance (%)95% CIs for the proportion were based on exact confidence limits using the Clopper-Pearson method. 60.0 (14.7, 94.7)100.0 (63.1, 100.0)Change in FACIT-Fatigue 3.4 (-4.2, 11.0)1.3 (-3.1, 5.7)Hemoglobin Stabilization (%) 60.0 (14.7, 94.7)75.0 (34.9, 96.8)Breakthrough Hemolysis (%)00No patients experienced breakthrough hemolysis during the primary evaluation period. One patient experienced breakthrough hemolysis at 1.8 years during the extension period; however, at the time of the BTH event the patient had adequate C5 inhibition (free C5 0.5 ug/mL). clinically relevant improvement from baseline in fatigue as assessed by Pediatric FACIT-Fatigue (i.e., mean improvement of 3 units for Pediatric FACIT Fatigue scores) was sustained throughout the primary evaluation period in the 5-complement inhibitor treatment naive patients. slight improvement was also observed in eculizumab-experienced patients. However, patient-reported fatigue may be an under-or over-estimation, because patients were not blinded to treatment assignment.The efficacy of ULTOMIRIS in pediatric patients with PNH is similar to that observed in adult patients with PNH enrolled in pivotal studies.. 14.2Atypical Hemolytic Uremic Syndrome (aHUS). The efficacy of ULTOMIRIS in patients with aHUS was assessed in open-label, single-arm studies. Study ALXN1210-aHUS-311 enrolled adult patients who displayed signs of TMA. In order to qualify for enrollment, patients were required to have platelet count <=150 109/L, evidence of hemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal or required dialysis.Study ALXN1210-aHUS-312 enrolled pediatric patients who displayed signs of TMA. In order to qualify for enrollment, patients were required to have platelet count <=150 109/L, evidence of hemolysis such as an elevation in serum LDH, and serum creatinine level >=97.5% percentile at screening or required dialysis. In both studies, enrollment criteria excluded patients presenting with TMA due to disintegrin and metalloproteinase with thrombospondin type motif, member 13 (ADAMTS13) deficiency, Shiga toxin Escherichia coli related hemolytic uremic syndrome (STEC-HUS) and genetic defect in cobalamin metabolism. Patients with confirmed diagnosis of STEC-HUS after enrollment were excluded from the efficacy evaluation.. Study in Adult Patients with aHUSThe adult study [ALXN1210-aHUS-311; NCT02949128] was conducted in patients who were naive to complement inhibitor treatment prior to study entry. The study consisted of 26-week Initial Evaluation Period and patients were allowed to enter an extension period for up to 4.5 years.A total of 56 patients with aHUS were evaluated for efficacy. Ninety-three percent of patients had extra-renal signs (cardiovascular, pulmonary, central nervous system, gastrointestinal, skin, skeletal muscle) or symptoms of aHUS at baseline. At baseline, 71.4% (n 40) of patients had Stage chronic kidney disease (CKD). Fourteen percent had medical history of kidney transplant and 51.8% were on dialysis at study entry. Eight patients entered the study with evidence of TMA for 3 days after childbirth (ie, postpartum).Table 19 presents the demographics and baseline characteristics of the 56 adult patients enrolled in Study ALXN1210-aHUS-311 that constituted the Full Analysis Set.Table 19:Demographics and Baseline Characteristics in Study ALXN1210-aHUS-311ParameterStatisticsULTOMIRIS (N=56)Note: Percentages are based on the total number of patients.eGFR estimated glomerular filtration rate; LDH lactate dehydrogenase; max maximum; min minimum.Age at time of first infusion (years)Mean (SD)Min, max42.2 (14.98)19.5, 76.6Sex Femalen (%)37 (66.1)Race Patients can have multiple races selected. (%) White29 (51.8) Asian15 (26.8) Unknown8 (14.3) Other4 (7.1)Platelets (109/L) blood[normal range 130 to 400 109/L]nMedian (min,max)5695.25 (18, 473)Hemoglobin (g/L) blood[normal range 115 to 160 g/L (female), 130 to 175 g/L (male)]nMedian (min,max)5685.00 (60.5, 140)LDH (U/L) serum[normal range 120 to 246 U/L]nMedian (min,max)56508.00 (229.5, 3249)eGFR (mL/min/1.73 m2)[normal range >= 60 mL/min/1.73 m2]n (%)Mean (SD)Median (min,max)5515.86 (14.815)10.00 (4, 80)The efficacy evaluation was based on Complete TMA Response during the 26-week Initial Evaluation Period, as evidenced by normalization of hematological parameters (platelet count and LDH) and >= 25% improvement in serum creatinine from baseline. Patients had to meet each Complete TMA Response criteria at separate assessments obtained at least weeks (28 days) apart, and any measurement in between.Complete TMA Response was observed in 30 of the 56 patients (54%) during the 26-week Initial Evaluation Period as shown in Table 20.Table 20:Efficacy Results in aHUS during the 26-Week Initial Evaluation Period (ALXN1210-aHUS-311)TotalRespondernProportion (95% CI)95% CIs for the proportion were based on exact confidence limits using the Clopper-Pearson method. CI confidence interval; LDH lactate dehydrogenase; TMA thrombotic microangiopathy.Complete TMA Response56300.54 (0.40, 0.67)Components of Complete TMA Response Platelet count normalization56470.84 (0.72, 0.92) LDH normalization56430.77 (0.64, 0.87) >=25% improvement in serum creatinine from baseline56330.59 (0.45, 0.72)Hematologic normalization56410.73 (0.60, 0.84)One additional patient had Complete TMA Response that was confirmed after the 26-week Initial Evaluation Period. Complete TMA Response was achieved at median time of 86 days (range: to 169 days). The median duration of Complete TMA Response was 7.97 months (range: 2.52 to 16.69 months). All responses were maintained through all available follow-up.Other endpoints included platelet count change from baseline, dialysis requirement, and renal function as evaluated by estimated glomerular filtration rate (eGFR).An increase in mean platelet count was observed after commencement of ULTOMIRIS, increasing from 118.52 109/L at baseline to 240.34 x109/L at Day and remaining above 227 109/L at all subsequent visits in the Initial Evaluation Period (26 weeks).Renal function, as measured by eGFR, was improved or maintained during ULTOMIRIS therapy. The mean eGFR (+/- SD) increased from 15.86 (14.82) at baseline to 51.83 (39.16) by 26 weeks. In patients with Complete TMA Response, renal function continued to improve after the Complete TMA Response was achieved .Seventeen of the 29 patients (59%) who required dialysis at study entry discontinued dialysis by the end of the available follow-up and of 27 (22%) patients were off dialysis at baseline were on dialysis at last available follow-up.. Study in Pediatric Patients with aHUSThe Pediatric Study [ALXN1210-aHUS-312; NCT03131219] is 26-week ongoing, multicenter, single-arm study conducted in 16 pediatric patients.A total of 14 eculizumab-naive patients with documented diagnosis of aHUS were enrolled and included in this interim analysis. The median age at the time of first infusion was 5.2 years (range 0.9, 17.3 years). The overall mean weight at Baseline was 19.8 kg; half of the patients were in the baseline weight category >= 10 to 20 kg. The majority of patients (71%) had pretreatment extra-renal signs (cardiovascular, pulmonary, central nervous system, gastrointestinal, skin, skeletal muscle) or symptoms of aHUS at baseline. At baseline, 35.7% (n 5) of patients had CKD Stage 5. Seven percent had history of prior kidney transplant and 35.7% were on dialysis at study entry.Table 21 presents the baseline characteristics of the pediatric patients enrolled in Study ALXN1210-aHUS-312.Table 21:Demographics and Baseline Characteristics in Study ALXN1210-aHUS-312ParameterStatisticsULTOMIRIS (N 14)Note: Percentages are based on the total number of patients.eGFR estimated glomerular filtration rate; LDH lactate dehydrogenase; max maximum; min minimum.Age at time of first infusion (years) categoryn (%) Birth to 2 years2 (14.3) to 6 years7 (50.0) to 12 years4 (28.6) 12 to 18 years1 (7.1)Sexn (%) Female9 (64.3)RacePatients can have multiple races selected. (%) White7 (50.0) Asian4 (28.6) Black or African American2 (14.3) American Indian or Alaskan Native1 (7.1) Unknown1 (7.1)Platelets (109/L) blood [normal range 229 to 533 109/L]Median (min, max)64.00 (14, 125)Hemoglobin (g/L) blood [normal range 107 to 131 g/L]Median (min, max)74.25 (32, 106)LDH (U/L) serum [normal range 165 to 395 U/L]Median (min, max)2077.00 (772, 4985)eGFR (mL/min/1.73 m2) [normal range >= 60 mL/min/1.73 m2]Mean (SD)Median (min, max)28.4 (23.11)22.0 (10, 84)Efficacy evaluation was based upon Complete TMA Response during the 26-week Initial Evaluation Period, as evidenced by normalization of hematological parameters (platelet count and LDH) and >= 25% improvement in serum creatinine from baseline. Patients had to meet all Complete TMA Response criteria at separate assessments obtained at least weeks (28 days) apart, and any measurement in between.Complete TMA Response was observed in 10 of the 14 patients (71%) during the 26-week Initial Evaluation Period as shown in Table 22.Table 22:Efficacy Results in aHUS during the 26-Week Initial Evaluation Period (ALXN1210-aHUS-312)TotalRespondernProportion (95% CI)95% CIs for the proportion were based on exact confidence limits using the Clopper-Pearson method. Note: patient withdrew from study after receiving doses of ravulizumab-cwvz.CI confidence interval; LDH lactate dehydrogenase; TMA thrombotic microangiopathy.Complete TMA Response14100.71 (0.42, 0.92)Components of Complete TMA Response Platelet count normalization14130.93 (0.66, 0.99) LDH normalization14120.86 (0.57, 0.98) >=25% improvement in serum creatinine from baseline14110.79 (0.49, 0.95)Hematologic normalization14120.86 (0.57, 0.98)Complete TMA Response during the Initial Evaluation Period was achieved at median time of 30 days (range:15 to 88 days). The median duration of Complete TMA Response was 5.08 months (range: 3.08 to 5.54 months). All responses were maintained through all available follow-up.Other endpoints included platelet count change from baseline, dialysis requirement, and renal function as evaluated by eGFR.An increase in mean platelet count was observed after commencement of ULTOMIRIS, increasing from 60.50 109/L at baseline to 296.67 109/L at Day and remained above 296 109/L at all subsequent visits in the Initial Evaluation Period (26 weeks). The mean eGFR (+/- SD) increased from 28.4 (23.11) at baseline to 108.0 (63.21) by 26 weeks.Four of the patients who required dialysis at study entry were able to discontinue dialysis after the first month in study and for the duration of ULTOMIRIS treatment. No patient started dialysis during the study.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 PNHThe data described below reflect exposure of 441 adult patients with PNH in Phase studies who received ULTOMIRIS (n 222) or eculizumab (n 219) at the recommended dosing regimens with median treatment duration of months for ULTOMIRIS and months for eculizumab. The most frequent adverse reactions (>=10%) with ULTOMIRIS were upper respiratory tract infection and headache. Table describes adverse reactions that occurred at 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 patient treated with ULTOMIRIS.One fatal case of sepsis was identified in patient treated with ULTOMIRIS.Table 6: Adverse Reactions Reported in 5% or More of ULTOMIRIS-Treated Patients in Complement Inhibitor Naive and Eculizumab-Experienced Adult Patients with PNHBody System Adverse ReactionNumber of PatientsULTOMIRIS (N=222) (%)Eculizumab (N=219) (%)Gastrointestinal disorders Diarrhea19 (9)12 (5) Nausea19 (9)19 (9) Abdominal pain13 (6)16 (7)General Disorders and Administration Site Conditions Pyrexia15 (7)18 (8)Infections and Infestations Upper respiratory tract infectionGrouped 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 extremity14 (6)11 (5) Arthralgia11 (5)12 (5)Nervous System Disorders Headache71 (32)57 (26) Dizziness12 (5)14 (6)Clinically relevant adverse reactions in 1% of patients include infusion-related reactions.. Pediatric population with PNHIn pediatric patients with PNH (aged to 17 years old) included in the pediatric PNH Phase 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 describes the adverse reactions that occurred at rate of 10% or more among pediatric patients treated with ULTOMIRIS in Study ALXN1210-PNH-304.Table 7: Adverse Reactions Reported in 10% or More of ULTOMIRIS-Treated Pediatric Patients with PNH in Study ALXN1210-PNH-304Body System Adverse ReactionTreatment Naive(N=5)Eculizumab Experienced(N=8)Total(N=13)n (%)n (%)n (%)Blood and lymphatic system disorders AnemiaGrouped term includes: anemia and iron deficiency anemia (20)2 (25)3 (23)Gastrointestinal disorders Abdominal pain0 (0)3 (38)3 (23) Constipation0 (0)2 (25)2 (15)General disorders and administration site conditions Pyrexia1 (20)1 (13)2 (15)Infections and infestations Upper Respiratory tract infectionGrouped term includes: nasopharyngitis, upper respiratory tract infection, oropharyngeal pain and viral upper respiratory tract infection (20)6 (75)7 (54)Musculoskeletal and connective tissue disorders Pain in extremity0 (0)2 (25)2 (15)Nervous system disorders Headache1 (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. Tables 8, and 10 describe adverse reactions that occurred at 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 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 two patients and intracranial hemorrhage in one patient. The fourth patient, who was excluded from the trial after diagnosis of STEC-HUS, died due to pretreatment cerebral arterial thrombosis.Table 8: Adverse Reactions Reported in >=10% of ULTOMIRIS-Treated Patients with aHUS in Study ALXN1210-aHUS-311Body System Adverse ReactionALXN1210-aHUS-311 (N=58)All Grades: Graded per CTCAE v5.0. (n=53) (%)>= Grade (n=14) (%)Blood and lymphatic system disorders Anemia8 (14)0 (0)Gastrointestinal disorders Diarrhea18 (31)2 (3) Nausea15 (26)2 (3) Vomiting15 (26)2 (3) Constipation8 (14)1 (2) Abdominal pain7 (12)1 (2)General disorders and administration site conditions Pyrexia11 (19)1 (2) Edema peripheral10 (17)0 (0) Fatigue8 (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 infection10 (17)5 (9) Gastrointestinal infection: Grouped term includes gastroenteritis, gastrointestinal infection, enterocolitis infectious,infectious colitis, and enterocolitis. (14)2 (3)Metabolism and nutrition disorders Hypokalemia6 (10)1 (2)Musculoskeletal and connective tissue disorders Arthralgia13 (22)0 (0) Back pain7 (12)1 (2) Muscle spasms6 (10)0 (0) Pain in extremity6 (10)0 (0)Nervous system disorders Headache23 (40)1 (2)Psychiatric disorders Anxiety8 (14)1 (2)Respiratory, thoracic and mediastinal disorders Cough10 (17)0 (0) Dyspnea10 (17)1 (2)Skin and subcutaneous tissue disorders Alopecia6 (10)0 (0) Dry skin6 (10)0 (0)Vascular disorders Hypertension14 (24)7 (12)Clinically relevant adverse reactions include viral tonsilitis (in <10% of patients) and infusion-related reactions (in 3% of patients).Table 9: Adverse Reactions Reported in >=10% of ULTOMIRIS-Treated Patients with aHUS in Study ALXN1210-aHUS-312Body System Adverse ReactionALXN1210-aHUS-312 (N=16)All Grades: Graded per CTCAE v5.0. (n=16) (%)>= Grade (n=6) (%)Blood and lymphatic system disorders Anemia2 (13)1 (6) Lymphadenopathy2 (13)0 (0)Gastrointestinal disorders Diarrhea6 (38)0 (0) Constipation4 (25)0 (0) Vomiting4 (25)1 (6) Abdominal pain3 (19)0 (0) Nausea2 (13)0 (0)General disorders and administration site conditions Pyrexia8 (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. (44)1 (6) Gastroenteritis viral2 (13)2 (13) Pneumonia2 (13)1 (6) Tonsillitis2 (13)0 (0)Injury, poisoning and procedural complications Contusion3 (19)0 (0)Investigations Vitamin decreased3 (19)0 (0)Metabolism and nutrition disorders Decreased appetite2 (13)0 (0) Iron deficiency2 (13)0 (0)Musculoskeletal and connective tissue disorders Myalgia3 (19)0 (0) Pain in extremity2 (13)0 (0)Nervous system disorders Headache5 (31)0 (0)Respiratory, thoracic and mediastinal disorders Cough3 (19)0 (0) Dyspnea2 (13)0 (0)Skin and subcutaneous tissue disorders Rash3 (19)0 (0)Vascular disorders Hypertension4 (25)1 (6) Hypotension2 (13)0 (0)Clinically relevant adverse reactions in <10% of patients include viral infection.Table 10: Adverse Reactions Reported in >=10% of ULTOMIRIS-Treated Patients from Birth to 16 Years of Age with aHUS in Study ALXN1210-aHUS-312Body System Adverse ReactionALXN1210-aHUS-312Age to <2 (N=2)Age to <12 (N=12)Age 12 to 16 (N=1)Total (N=15)n (%)n (%)n (%)n (%)Blood and lymphatic system disorders Lymphadenopathy0 (0)2 (17)0 (0)2 (13)Gastrointestinal disorders Diarrhea1 (50)3 (25)1 (100)5 (33) Constipation0 (0)4 (33)0 (0)4 (27) Vomiting0 (0)3 (25)0 (0)3 (20) Abdominal pain0 (0)2 (17)0 (0)2 (13)General disorders and administration site conditions Pyrexia1 (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 (50)6 (50)0 (0)7 (47) Gastroenteritis viral0 (0)2 (17)0 (0)2 (13) Tonsillitis1 (50)1 (8)0 (0)2 (13)Injury, poisoning and procedural complications Contusion0 (0)2 (17)0 (0)2 (13)Investigations Vitamin decreased0 (0)2 (17)1 (100)3 (20)Metabolism and nutrition disorders Decreased appetite1 (50)1 (8)0 (0)2 (13) Iron deficiency0 (0)2 (17)0 (0)2 (13)Musculoskeletal and connective tissue disorders Myalgia1 (50)1 (8)0 (0)2 (13) Pain in extremity0 (0)2 (17)0 (0)2 (13)Nervous system disorders Headache0 (0)4 (33)0 (0)4 (27)Respiratory, thoracic and mediastinal disorders Cough0 (0)3 (25)0 (0)3 (20) Dyspnea1 (50)1 (8)0 (0)2 (13)Skin and subcutaneous tissue disorders Rash1 (50)2 (17)0 (0)3 (20)Vascular disorders Hypertension1 (50)3 (25)0 (0)4 (27) Hypotension0 (0)2 (17)0 (0)2 (13)Clinically relevant adverse reactions in <10% of patients include viral infection.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. ULTOMIRIS is contraindicated in:Patients with unresolved Neisseria meningitidis infection [see Warnings and Precautions (5.1)].Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying ULTOMIRIS treatment outweigh the risks of developing meningococcal infection [see Warnings and Precautions (5.1)].. Patients with unresolved Neisseria meningitidis infection [see Warnings and Precautions (5.1)].. Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying ULTOMIRIS treatment outweigh the risks of developing meningococcal infection [see Warnings and Precautions (5.1)].. ULTOMIRIS is contraindicated in:Patients with unresolved Neisseria Meningitidis infection (4).Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying ULTOMIRIS treatment outweigh the risks of developing meningococcal infection (4, 5.1).. Patients with unresolved Neisseria Meningitidis infection (4).. Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying ULTOMIRIS treatment outweigh the risks of developing meningococcal infection (4, 5.1).

DESCRIPTION SECTION.

11 DESCRIPTION. Ravulizumab-cwvz, complement inhibitor, is humanized monoclonal antibody (mAb) produced in Chinese hamster ovary (CHO) cells. Ravulizumab-cwvz consists of identical 448 amino acid heavy chains and identical 214 amino acid light chains and has molecular weight of approximately 148 kDa. The constant regions of ravulizumab-cwvz include the human kappa light chain constant region, and the protein engineered IgG2/4 heavy chain constant region.The heavy chain CH1 domain, hinge region, and the first amino acids of the CH2 domain match the human IgG2 amino acid sequence, residues to 36 in the CH2 region (common to both human IgG2 and IgG4 amino acid sequences), while the remainder of the CH2 domain and the CH3 domain match the human IgG4 amino acid sequence. The heavy and light chain variable regions that form the human C5 binding site consist of human framework regions grafted to murine complementarity-determining regions.. ULTOMIRIS 100 mg/mL (3 mL and 11 mL vials)ULTOMIRIS (ravulizumab-cwvz) injection 100 mg/mL is sterile, translucent, clear to yellowish color, preservative-free solution for intravenous use. Each single-dose vial contains 300 mg or 1,100 mg ravulizumab-cwvz at concentration of 100 mg/mL with pH of 7.4. Each mL also contains L-arginine (4.33 mg), polysorbate 80 (0.5 mg) (vegetable origin), sodium phosphate dibasic (4.42 mg), sodium phosphate monobasic (4.57 mg), sucrose (50 mg) and Water for Injection, USP.. ULTOMIRIS 10 mg/mL (30 mL vial)ULTOMIRIS (ravulizumab-cwvz) injection 10 mg/mL is sterile, clear to translucent, slight whitish color, preservative-free solution for intravenous use. Each single-dose vial contains 300 mg ravulizumab-cwvz at concentration of 10 mg/mL with pH of 7.0. Each mL also contains polysorbate 80 (0.2 mg) (vegetable origin), sodium chloride (8.77 mg), sodium phosphate dibasic (1.78 mg), sodium phosphate monobasic (0.46 mg), and Water for Injection, USP.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. See Full Prescribing Information for instructions on dosage, preparation, and administration (2.1, 2.2, 2.3, 2.4).. 2.1Recommended Vaccination and Prophylaxis. Vaccinate patients for meningococcal disease according to current ACIP guidelines to reduce the risk of serious infection [see Warnings and Precautions (5.1, 5.2)].Provide weeks of antibacterial drug prophylaxis to patients if ULTOMIRIS must be initiated immediately and vaccines are administered less than weeks before starting ULTOMIRIS therapy.Healthcare professionals who prescribe ULTOMIRIS must enroll in the ULTOMIRIS REMS [see Warnings and Precautions (5.1)].. 2.2Recommended Weight-Based Dosage Regimen PNH and aHUS. The recommended dosing regimen in adult and pediatric patients, one month of age or older weighing kg or greater, with PNH and aHUS consists of loading dose followed by maintenance dosing, administered by intravenous infusion. The dosing is based on the patients body weight, as shown in Table 1. Starting weeks after the loading dose administration, begin maintenance doses once every or weeks, based on body weight.The dosing schedule is allowed to occasionally vary within days of the scheduled infusion day (except for the first maintenance dose of ULTOMIRIS); but the subsequent doses should be administered according to the original schedule.Table 1: ULTOMIRIS Weight-Based Dosing Regimen PNH and aHUSBody Weight Range (kg)Loading Dose (mg)Maintenance Dose (mg) and Dosing Interval5 to less than 10600300Every weeks10 to less than 2060060020 to less than 309002,100Every weeks30 to less than 401,2002,70040 to less than 602,4003,00060 to less than 1002,7003,300100 or greater3,0003,600. 2.3Dosing Considerations. For patients switching from eculizumab to ULTOMIRIS, administer the loading dose of ULTOMIRIS weeks after the last eculizumab infusion, and then administer ULTOMIRIS maintenance doses once every weeks or every weeks (depending on body weight), starting weeks after loading dose administration.Administration of PE/PI (plasmapheresis or plasma exchange, or fresh frozen plasma infusion) may reduce ULTOMIRIS serum levels. There is no experience with administration of supplemental doses of ULTOMIRIS.. 2.4Preparation and Administration. Preparation of ULTOMIRISEach vial of ULTOMIRIS is intended for single-dose only.Do not mix ULTOMIRIS 100 mg/mL (3 mL and 11 mL vials) and 10 mg/mL (30 mL vial) concentrations together.Use aseptic technique to prepare ULTOMIRIS as follows:The number of vials to be diluted is determined based on the individual patients weight and the prescribed dose [see Dosage and Administration (2.2)].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.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 final concentration of: 50 mg/mL for the mL and 11 mL vial sizes or5 mg/mL for the 30 mL vial size. The product should be mixed gently. Do not shake. Protect from light. Do not freeze. Refer to the following reference tables for preparation: ULTOMIRIS 100 mg/mL (3 mL and 11 mL vials): see Table (loading doses) and Table (maintenance doses) ULTOMIRIS 10 mg/mL (30 mL vial): see Table (loading doses) and Table (maintenance doses) Administer the prepared solution immediately following preparation. Refer to Table (loading doses) and Table (maintenance doses) for ULTOMIRIS 100 mg/mL (3 mL and 11 mL vials) and Table (loading doses) and Table (maintenance doses) for ULTOMIRIS 10 mg/mL (30 mL vial) for minimum infusion duration. Infusion must be administered through 0.2 or 0.22 micron filter.If the diluted ULTOMIRIS infusion solution is not used immediately, storage under refrigeration at 2C 8C (36F 46F) must not exceed 24 hours taking into account the expected infusion time. Once removed from refrigeration, administer the diluted ULTOMIRIS infusion solution within hours if prepared with ULTOMIRIS 30 mL vials or within hours if prepared with ULTOMIRIS mL or 11 mL vials.. The number of vials to be diluted is determined based on the individual patients weight and the prescribed dose [see Dosage and Administration (2.2)].. 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.. 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 final concentration of: 50 mg/mL for the mL and 11 mL vial sizes or5 mg/mL for the 30 mL vial size. The product should be mixed gently. Do not shake. Protect from light. Do not freeze. Refer to the following reference tables for preparation: ULTOMIRIS 100 mg/mL (3 mL and 11 mL vials): see Table (loading doses) and Table (maintenance doses) ULTOMIRIS 10 mg/mL (30 mL vial): see Table (loading doses) and Table (maintenance doses) 50 mg/mL for the mL and 11 mL vial sizes or. mg/mL for the 30 mL vial size.. Administer the prepared solution immediately following preparation. Refer to Table (loading doses) and Table (maintenance doses) for ULTOMIRIS 100 mg/mL (3 mL and 11 mL vials) and Table (loading doses) and Table (maintenance doses) for ULTOMIRIS 10 mg/mL (30 mL vial) for minimum infusion duration. Infusion must be administered through 0.2 or 0.22 micron filter.. If the diluted ULTOMIRIS infusion solution is not used immediately, storage under refrigeration at 2C 8C (36F 46F) must not exceed 24 hours taking into account the expected infusion time. Once removed from refrigeration, administer the diluted ULTOMIRIS infusion solution within hours if prepared with ULTOMIRIS 30 mL vials or within hours if prepared with ULTOMIRIS mL or 11 mL vials.. Administration of ULTOMIRISOnly administer as an intravenous infusion.Dilute ULTOMIRIS to final concentration of:50 mg/mL for the mL and 11 mL vial sizes or5 mg/mL for the 30 mL vial size.Administer ULTOMIRIS only through 0.2 or 0.22 micron filter.Table 2:Loading Dose Reference Table for ULTOMIRIS 100 mg/mL (3 mL and 11 mL vials)Body Weight Range (kg) Body weight at time of treatment. Loading Dose (mg)ULTOMIRIS Volume (mL)Volume of NaCl DiluentDilute 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 1060066121.4810 to less than 2060066120.81620 to less than 3090099180.63030 to less than 401,2001212240.54640 to less than 602,4002424480.86460 to less than 1002,7002727540.692100 or greater3,0003030600.4144Table 3: Maintenance Dose Reference Table for ULTOMIRIS 100 mg/mL (3 mL and 11 mL vials)Body Weight Range (kg) Body weight at time of treatment. Maintenance Dose (mg)ULTOMIRIS Volume (mL)Volume of NaCl DiluentDilute 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 103003360.8810 to less than 2060066120.81620 to less than 302,1002121421.33330 to less than 402,7002727541.14940 to less than 603,0003030600.96560 to less than 1003,3003333660.799100 or greater3,6003636720.5144Table 4:Loading Dose Reference Table for ULTOMIRIS 10 mg/mL (30 mL vial)Body Weight Range (kg)Body weight at time of treatment. Loading Dose (mg)ULTOMIRIS Volume (mL)Volume of NaCl DiluentDilute 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 1060060601203.83110 to less than 2060060601201.96320 to less than 3090090901801.512030 to less than 401,2001201202401.318440 to less than 602,4002402404801.925260 to less than 1002,7002702705401.7317100 or greater3,0003003006001.8333Table 5: Maintenance Dose Reference Table for ULTOMIRIS 10 mg/mL (30 mL vial)Body Weight Range (kg)Body weight at time of treatment. Maintenance Dose (mg)ULTOMIRIS Volume (mL)Volume of NaCl DiluentDilute 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 103003030601.93110 to less than 2060060601201.96320 to less than 302,1002102104203.312730 to less than 402,7002702705402.819240 to less than 603,0003003006002.325760 to less than 1003,3003303306602330100 or greater3,6003603607202.2327Prior to administration, allow the admixture to adjust to room temperature (18C 25C, 64F 77F). Do not heat the admixture in 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.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 one hour following completion of the infusion for signs or symptoms of an infusion-related reaction.. 50 mg/mL for the mL and 11 mL vial sizes or. mg/mL for the 30 mL vial size.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection:300 mg/30 mL (10 mg/mL) in single-dose vial (3).300 mg/3 mL (100 mg/mL) in single-dose vial (3).1,100 mg/11 mL (100 mg/mL) in single-dose vial (3).. ULTOMIRIS 100 mg/mLInjection: 300 mg/3 mL (100 mg/mL) and 1,100 mg/11 mL (100 mg/mL) as translucent, clear to yellowish color solution in single-dose vial.. ULTOMIRIS 10 mg/mLInjection: 300 mg/30 mL (10 mg/mL) as clear to translucent, slight whitish color solution in single-dose vial.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of ULTOMIRIS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. ULTOMIRIS (ravulizumab-cwvz) injection 100 mg/mL is translucent, clear to yellowish color solution supplied in single-dose vials as:300 mg/3 mL (100 mg/mL) carton containing one vial: NDC 25682-025-011,100 mg/11 mL (100 mg/mL) carton containing one vial: NDC 25682-028-01ULTOMIRIS (ravulizumab-cwvz) injection 10 mg/mL is clear to translucent, slight whitish color solution supplied in single-dose vials as:300 mg/30 mL (10 mg/mL) carton containing one vial: NDC 25682-022-01. 300 mg/3 mL (100 mg/mL) carton containing one vial: NDC 25682-025-01. 1,100 mg/11 mL (100 mg/mL) carton containing one vial: NDC 25682-028-01. 300 mg/30 mL (10 mg/mL) carton containing one vial: NDC 25682-022-01. Store ULTOMIRIS vials refrigerated at 2C 8C (36F 46F) in the original carton to protect from light. Do not freeze. Do not shake.Refer to Dosage and Administration (2) for information on the stability and storage of diluted solutions of ULTOMIRIS.

IMMUNOGENICITY.

6.2 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibodies) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other ravulizumab-cwvz products may be misleading.The immunogenicity of ravulizumab-cwvz has been evaluated using an enzyme-linked immunosorbent assay (ELISA) for the detection of binding anti-ravulizumab-cwvz antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies.In clinical studies, treatment-emergent antibodies to ravulizumab-cwvz were detected in of 219 (0.5%) patients with PNH and of 71 (1.4%) patients with aHUS. In these patients, no apparent correlation of antibody development to altered pharmacokinetic profile, clinical response, or adverse events was observed. However, the assay used to measure anti-drug antibodies (ADA) is subject to interference by serum ravulizumab-cwvz, possibly resulting in an underestimation of the incidence of antibody formation. Due to the limitation of the assay conditions, the potential clinical impact of antibodies to ravulizumab-cwvz is not known.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. ULTOMIRIS is indicated for:the treatment of adult and pediatric patients one month of age and older with paroxysmal nocturnal hemoglobinuria (PNH).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).. the treatment of adult and pediatric patients one month of age and older with paroxysmal nocturnal hemoglobinuria (PNH).. 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).. ULTOMIRIS is complement inhibitor indicated for:the treatment of adult and pediatric patients one month of age and older with paroxysmal nocturnal hemoglobinuria (PNH) (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).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 and pediatric patients one month of age and older with paroxysmal nocturnal hemoglobinuria (PNH) (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).. Limitations of Use:ULTOMIRIS is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read FDA-approved patient labeling (Medication Guide).. Meningococcal InfectionAdvise patients of the risk of meningococcal infection/sepsis. Inform patients that they are required to receive meningococcal vaccination at least weeks prior to receiving the first dose of ULTOMIRIS, if they have not previously been vaccinated. They are required to be revaccinated according to current medical guidelines for meningococcal vaccines use while on ULTOMIRIS therapy. Inform patients that vaccination may not prevent meningococcal infection. Inform patients about the signs and symptoms of meningococcal infection/sepsis, and strongly advise patients to seek immediate medical attention if these signs or symptoms occur. These signs and symptoms are as follows:headache with nausea or vomitingheadache and feverheadache with stiff neck or stiff backfeverfever and rashconfusionmuscle aches with flu-like symptomseyes sensitive to lightInform patients that they will be given an ULTOMIRIS Patient Safety Card that they should carry with them at all times. This card describes symptoms which, if experienced, should prompt the patient to immediately seek medical evaluation.. headache with nausea or vomiting. headache and fever. headache with stiff neck or stiff back. fever. fever and rash. confusion. muscle aches with flu-like symptoms. eyes sensitive to light. Other InfectionsCounsel patients of the increased risk of infections, particularly those due to encapsulated bacteria, especially Neisseria species. Advise patients of the need for vaccination against meningococcal infections according to current medical guidelines. Counsel patients about gonorrhea prevention and advise regular testing for patients at risk. Advise patients to report any new signs and symptoms of infection.. DiscontinuationInform patients with PNH or aHUS that they may develop hemolysis or TMA, respectively, when ULTOMIRIS is discontinued and that they will be monitored by their healthcare professional for at least 16 weeks for PNH or at least 12 months for aHUS following ULTOMIRIS discontinuation.Inform patients who discontinue ULTOMIRIS to keep the ULTOMIRIS Patient Safety Card with them for eight months after the last ULTOMIRIS dose, because the increased risk of meningococcal infection persists for several weeks following discontinuation of ULTOMIRIS.. Infusion-Related ReactionsAdvise patients that administration of ULTOMIRIS may result in infusion-related reactions.

LACTATION SECTION.

8.2 Lactation. Risk summaryThere are no data on the presence of ravulizumab-cwvz in human milk, the effect on the breastfed child, or the effect on milk production. Since many medicinal products and immunoglobulins are secreted into human milk, and because of the potential for serious adverse reactions in nursing child, breastfeeding should be discontinued during treatment and for months after the final dose.

MECHANISM OF ACTION SECTION.

12.1Mechanism of Action. Ravulizumab-cwvz is 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 terminal complement complex [C5b-9]) and preventing the generation of the terminal complement complex C5b9. ULTOMIRIS inhibits terminal complement-mediated intravascular hemolysis in patients with PNH and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term animal carcinogenicity studies of ravulizumab-cwvz have not been conducted.Genotoxicity studies have not been conducted with ravulizumab-cwvz.Effects of ravulizumab-cwvz upon fertility have not been studied in animals. Intravenous injections of male and female mice with murine anti-C5 antibody at up to 0.8-2.2 times the equivalent of the clinical dose of ULTOMIRIS had no adverse effects on mating or fertility.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 30 mL Vial Carton. NDC 25682-022-01ULTOMIRIS(R) (ravulizumab-cwvz) injection300 mg/30 mL (10 mg/mL)For Intravenous InfusionDilute with 0.9% Sodium Chloride Injection prior to use.Rx only30 mL Single-dose vialDiscard Unused PortionAttention: Dispense the enclosed Medication Guide to each patient.. PRINCIPAL DISPLAY PANEL 30 mL Vial Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of ULTOMIRIS for the treatment of PNH have been established in pediatric patients aged one month and older. Use of ULTOMIRIS for this indication is supported by evidence from adequate and well-controlled trials in adults with additional pharmacokinetic, efficacy and safety data in pediatric patients aged to 17 years [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)]. The safety and efficacy for the treatment of pediatric and adult patients with PNH appear similar. Use of ULTOMIRIS in pediatric patients with PNH aged less than years and body weight <30 kg is based on extrapolation of pharmacokinetic pharmacodynamic (PK/PD), and efficacy and safety data from aHUS and PNH clinical studies [see Clinical Pharmacology (12.3) and Clinical Studies (14)].The safety and effectiveness of ULTOMIRIS for the treatment of aHUS have been established in pediatric patients aged one month and older. Use of ULTOMIRIS for this indication is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic, safety, and efficacy data in pediatric patients aged 10 months to <17 years. The safety and efficacy of ULTOMIRIS for the treatment of aHUS appear similar in pediatric and adult patients [see Adverse Reactions (6.1), and Clinical Studies (14.2)].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Complete inhibition of serum free C5 (concentration of less than 0.5 mcg/mL) was observed by the end of the first ULTOMIRIS infusion and sustained throughout the entire 26-week treatment period in both adult and pediatric patients with PNH and in the majority (93%) of adult and pediatric patients with aHUS.The extent and duration of the pharmacodynamic response in patients with PNH and aHUS were exposure-dependent for ULTOMIRIS. Free C5 levels of <0.5 mcg/mL were correlated with maximal intravascular hemolysis control and complete terminal complement inhibition in patients with PNH.Complete terminal complement inhibition following initiation of ULTOMIRIS treatment led to normalization of serum LDH by week in complement-inhibitor naive patients with PNH, and maintained LDH normalization in patients previously treated with eculizumab with PNH [see Clinical Studies (14)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Ravulizumab-cwvz pharmacokinetics increase proportionally over dose range of 200 to 5400 mg. Ravulizumab-cwvz Cmax and Ctrough parameters are presented in Table 11 and Table 12.Table 11: Mean (%CV) Pharmacokinetic Parameters of ULTOMIRIS in Patients with PNH who are Complement Inhibitor-Naive and Patients Previously Treated with EculizumabPediatric PatientsAdult PatientsALXN1210-PNH-304ALXN1210-PNH-301ALXN1210-PNH-302NComplement Inhibitor- NaiveNPreviously Treated with EculizumabNComplement Inhibitor- NaiveNPreviously Treated with EculizumabLD Loading Dose; MD Maintenance DoseLD4733 (14.5)8885 (19.3)125771 (21.5)95843 (24.1)Cmax (mcg/mL)MD41490 (26.7)81705 (9.7)1241,379 (20.0)951,386 (19.4)Ctrough (mcg/mL)LD4368 (14.7)8452 (15.1)125391 (35.0)96405 (29.9)MD4495 (21.3)8566 (12.2)124473 (33.4)95501 (28.6)Table 12: Mean (%CV) Pharmacokinetic Parameters of ULTOMIRIS in Patients with aHUSPediatric Patients (ALXN1210-aHUS-312)Adult Patients (ALXN1210-aHUS-311)N< 20 kg MD Q4WN>= 20 to 40 kg MD Q8WN>= 40 kg MD Q8WLD Loading Dose; MD Maintenance Dose; Q4W Every Weeks; Q8W Every WeeksCmax (mcg/mL)LD8656 (38.1)4600 (17.3)52754 (35.2)MD71,467 (37.8)61,863 (15.3)461,458 (17.6)Ctrough (mcg/mL)LD9241 (52.1)5186 (16.5)55313 (33.9)MD7683 (46.1)6549 (34.1)46507 (42.5). DistributionThe mean (%CV) volume of distribution at steady state was 5.30 (17.9) and 5.22 (35.4) in patients with PNH and aHUS, respectively.. EliminationThe mean (%CV) terminal elimination half-life of ravulizumab-cwvz was 49.6 (18.3) days and 51.8 (31.3) days in patients with PNH and aHUS, respectively. The mean (%CV) clearance of ravulizumab-cwvz was 0.08 (28.1) L/day and 0.08 (53.3) L/day in patients with PNH and aHUS, respectively.. Specific PopulationsNo 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 clinically significant covariate on the pharmacokinetics of ravulizumab-cwvz.

POSTMARKETING EXPERIENCE SECTION.

6.3 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of ULTOMIRIS. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to ULTOMIRIS exposure.Serious Adverse Reaction: Anaphylaxis.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no available data on ULTOMIRIS use in pregnant women to inform drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated PNH and aHUS in pregnancy (see Clinical Considerations ). Animal studies using mouse analogue of the ravulizumab-cwvz molecule (murine anti-C5 antibody) showed increased rates of developmental abnormalities and an increased rate of dead and moribund offspring at doses 0.8-2.2 times the human dose (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Clinical Considerations. Disease-associated maternal and/or fetal/neonatal riskPNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages, and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery.In pregnancy, aHUS is associated with adverse maternal outcomes, including preeclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including intrauterine growth restriction (IUGR), fetal death and low birth weight.. Data. Animal DataAnimal reproduction studies were conducted in mice using doses of murine anti-C5 antibody that approximated 1-2.2 times (loading dose) and 0.8-1.8 times (maintenance dose) the recommended human ULTOMIRIS dose, based on body weight comparison. When animal exposure to the antibody occurred in the time period from before mating until early gestation, no decrease in fertility or reproductive performance was observed. When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death. When maternal exposure to the antibody occurred in the time period from implantation through weaning, higher number of male offspring became moribund or died (1/25 controls, 2/25 low dose group, 5/25 high dose group). Surviving offspring had normal development and reproductive function. Human IgG are known to cross the human placental barrier, and thus ULTOMIRIS may potentially cause terminal complement inhibition in fetal circulation.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1)06/2021Dosing and Administration (2.2)06/2021.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 06/2021 MEDICATION GUIDEULTOMIRIS(R) (ul-toe-meer-is) (ravulizumab-cwvz) injection, for intravenous useWhat is the most important information should know about ULTOMIRISULTOMIRIS is medicine that affects your immune system. ULTOMIRIS can lower the ability of your immune system to fight infections.ULTOMIRIS increases your chance of getting serious and life-threatening meningococcal infections. Meningococcal infections may quickly become life-threatening and cause death if not recognized and treated early.You must receive meningococcal vaccines at least weeks before your first dose of ULTOMIRIS if you have not already had this vaccine.If your doctor decided that urgent treatment with ULTOMIRIS is needed, you should receive meningococcal vaccination as soon as possible.If you have not been vaccinated and ULTOMIRIS therapy must be initiated immediately, you should also receive weeks of antibiotics with your vaccinations.If you had meningococcal vaccine in the past, you might need additional vaccination before starting ULTOMIRIS. Your doctor will decide if you need additional meningococcal vaccination.Meningococcal vaccines reduce the risk of meningococcal infection but do not prevent all meningococcal infections. Call your doctor or get emergency medical care right away if you get any of these signs and symptoms of meningococcal infection:headache with nausea or vomitingheadache with stiff neck or stiff backfever and rashmuscle aches with flu-like symptomsheadache and feverfeverconfusioneyes sensitive to lightYour doctor will give you Patient Safety Card about the risk of meningococcal infection. Carry it with you at all times during treatment and for months after your last ULTOMIRIS dose. Your risk of meningococcal infection may continue for several months after your last dose of ULTOMIRIS. It is important to show this card to any doctor or nurse who treats you. This will help them diagnose and treat you quickly.ULTOMIRIS is only available through program called the ULTOMIRIS REMS. Before you can receive ULTOMIRIS, your doctor must:enroll in the ULTOMIRIS REMS programcounsel you about the risk of meningococcal infectiongive you information about the symptoms of meningococcal infectiongive you Patient Safety Card about your risk of meningococcal infection, as discussed abovemake sure that you are vaccinated with meningococcal vaccine, and if needed, get revaccinated with the meningococcal vaccine. Ask your doctor if you are not sure if you need to be revaccinated. ULTOMIRIS may also increase the risk of other types of serious infections.People who take ULTOMIRIS may have an increased risk of getting infections caused by Streptococcus pneumoniae and Haemophilus influenzae.If your child is treated with ULTOMIRIS, make sure that your child receives vaccinations against Streptococcus pneumoniae and Haemophilis influenzae type (Hib).Certain people may also have an increased risk of gonorrhea infection. Talk to your doctor to find out if you are at risk for gonorrhea infection, about gonorrhea prevention, and regular testing.Call your doctor right away if you have any new signs or symptoms of infection.What is ULTOMIRISULTOMIRIS is prescription medicine called monoclonal antibody. ULTOMIRIS is used to treat:adults and children month of age and older with disease called Paroxysmal Nocturnal Hemoglobinuria (PNH).adults and children month of age and older with disease called atypical hemolytic uremic syndrome (aHUS). ULTOMIRIS is not used in treating people with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). It is not known if ULTOMIRIS is safe and effective in children younger than month of age.Who should not receive ULTOMIRISDo not receive ULTOMIRIS if you:have meningococcal infectionhave not been vaccinated against meningococcal infection unless your doctor decides that urgent treatment with ULTOMIRIS is needed. See What is the most important information should know about ULTOMIRIS. Before you receive ULTOMIRIS, tell your doctor about all of your medical conditions, including if you:have an infection or feverare pregnant or plan to become pregnant. It is not known if ULTOMIRIS will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if ULTOMIRIS passes into your breast milk. You should not breastfeed during treatment and for months after your final dose of ULTOMIRIS.Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. ULTOMIRIS and other medicines can affect each other causing side effects.Know the medicines you take and the vaccines you receive. Keep list of them to show your doctor and pharmacist when you get new medicine.How should receive ULTOMIRISULTOMIRIS is given through vein by intravenous (I.V.) infusionIf you are an adult with PNH or aHUS, you will usually receive:a starting dose of ULTOMIRIS as an infusion by your doctor, and then2 weeks later, you will start to receive an infusion of ULTOMIRIS every weeks. Children month of age and older with PNH or aHUS will usually receive:a starting dose of ULTOMIRIS as an infusion by your doctor, and thenyour doctor will decide how often your child will receive ULTOMIRIS, either every weeks or every weeks, depending on their weight, starting weeks after the starting dose. Your doctor will decide how long you need to take ULTOMIRIS for your PNH or your aHUS.If you are changing treatment from SOLIRIS to ULTOMIRIS, you should receive your starting dose of ULTOMIRIS weeks after your last dose of SOLIRIS.After each infusion, you should be monitored for at least hour for infusion reactions. See What are the possible side effects of ULTOMIRIS If you have PNH and you stop receiving ULTOMIRIS, your doctor will need to monitor you closely for at least 16 weeks after you stop ULTOMIRIS. Stopping ULTOMIRIS may cause breakdown of your red blood cells due to PNH. Symptoms or problems that can happen due to red blood cell breakdown include: drop in your red blood cell counttirednessblood in your urinestomach-area (abdomen) painshortness of breathblood clotstrouble swallowingerectile dysfunction (ED) in malesIf you have aHUS, your doctor will need to monitor you closely for at least 12 months after stopping treatment for signs of worsening aHUS or problems related to type of abnormal clotting and breakdown of your red blood cells called thrombotic microangiopathy (TMA). Symptoms or problems that can happen with TMA may include:confusion or loss of consciousnessseizureschest pain (angina)difficulty breathingblood clots or strokeIf you miss an ULTOMIRIS infusion, call your doctor right away.What are the possible side effects of ULTOMIRISULTOMIRIS can cause serious side effects including:See What is the most important information should know about ULTOMIRIS Infusion-related reactions. Infusion-related reactions may happen during your ULTOMIRIS infusion. Symptoms of an infusion-related reaction with ULTOMIRIS may include lower back pain, feeling faint, or discomfort in your arms or legs. Tell your doctor or nurse right away if you develop these symptoms, or any other symptoms during your ULTOMIRIS infusion that may mean you are having serious infusion reaction, including:chest paintrouble breathing or shortness of breathswelling of your face, tongue, or throatfeel faint or pass out Your doctor will treat your symptoms as needed.The most common side effects of ULTOMIRIS in people treated for PNH are:upper respiratory tract infectionheadacheThe most common side effects of ULTOMIRIS in people treated for aHUS are:upper respiratory tract infectiondiarrheanauseavomitingheadachehigh blood pressurefeverTell your doctor about any side effect that bothers you or that does not go away.These are not all the possible side effects of ULTOMIRIS. For more information, ask your doctor or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of ULTOMIRIS.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. You can ask your pharmacist or doctor for information about ULTOMIRIS that is written for health professionals.What are the ingredients in ULTOMIRISActive ingredient: ravulizumab-cwvzInactive ingredients:ULTOMIRIS 100 mg/mL: L-arginine, polysorbate 80 (vegetable origin), sodium phosphate dibasic, sodium phosphate monobasic, sucrose and Water for InjectionULTOMIRIS 10 mg/mL: polysorbate 80 (vegetable origin), sodium chloride, sodium phosphate dibasic, sodium phosphate monobasic and Water for InjectionManufactured by Alexion Pharmaceuticals, Inc., 121 Seaport Boulevard, Boston, MA 02210 USA. U.S. License Number 1743For more information, go to www.ULTOMIRIS.com or call: 1-888-765-4747. ULTOMIRIS increases your chance of getting serious and life-threatening meningococcal infections. Meningococcal infections may quickly become life-threatening and cause death if not recognized and treated early.. You must receive meningococcal vaccines at least weeks before your first dose of ULTOMIRIS if you have not already had this vaccine.. If your doctor decided that urgent treatment with ULTOMIRIS is needed, you should receive meningococcal vaccination as soon as possible.. If you have not been vaccinated and ULTOMIRIS therapy must be initiated immediately, you should also receive weeks of antibiotics with your vaccinations.. If you had meningococcal vaccine in the past, you might need additional vaccination before starting ULTOMIRIS. Your doctor will decide if you need additional meningococcal vaccination.. Meningococcal vaccines reduce the risk of meningococcal infection but do not prevent all meningococcal infections. Call your doctor or get emergency medical care right away if you get any of these signs and symptoms of meningococcal infection:. headache with nausea or vomiting. headache with stiff neck or stiff back. fever and rash. muscle aches with flu-like symptoms. headache and fever. fever. confusion. eyes sensitive to light. enroll in the ULTOMIRIS REMS program. counsel you about the risk of meningococcal infection. give you information about the symptoms of meningococcal infection. give you Patient Safety Card about your risk of meningococcal infection, as discussed above. make sure that you are vaccinated with meningococcal vaccine, and if needed, get revaccinated with the meningococcal vaccine. Ask your doctor if you are not sure if you need to be revaccinated.. People who take ULTOMIRIS may have an increased risk of getting infections caused by Streptococcus pneumoniae and Haemophilus influenzae.. If your child is treated with ULTOMIRIS, make sure that your child receives vaccinations against Streptococcus pneumoniae and Haemophilis influenzae type (Hib).. Certain people may also have an increased risk of gonorrhea infection. Talk to your doctor to find out if you are at risk for gonorrhea infection, about gonorrhea prevention, and regular testing.. adults and children month of age and older with disease called Paroxysmal Nocturnal Hemoglobinuria (PNH).. adults and children month of age and older with disease called atypical hemolytic uremic syndrome (aHUS). ULTOMIRIS is not used in treating people with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).. have meningococcal infection. have not been vaccinated against meningococcal infection unless your doctor decides that urgent treatment with ULTOMIRIS is needed. See What is the most important information should know about ULTOMIRIS. have an infection or fever. are pregnant or plan to become pregnant. It is not known if ULTOMIRIS will harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if ULTOMIRIS passes into your breast milk. You should not breastfeed during treatment and for months after your final dose of ULTOMIRIS.. ULTOMIRIS is given through vein by intravenous (I.V.) infusion. starting dose of ULTOMIRIS as an infusion by your doctor, and then. weeks later, you will start to receive an infusion of ULTOMIRIS every weeks.. starting dose of ULTOMIRIS as an infusion by your doctor, and then. your doctor will decide how often your child will receive ULTOMIRIS, either every weeks or every weeks, depending on their weight, starting weeks after the starting dose.. If you are changing treatment from SOLIRIS to ULTOMIRIS, you should receive your starting dose of ULTOMIRIS weeks after your last dose of SOLIRIS.. After each infusion, you should be monitored for at least hour for infusion reactions. See What are the possible side effects of ULTOMIRIS If you have PNH and you stop receiving ULTOMIRIS, your doctor will need to monitor you closely for at least 16 weeks after you stop ULTOMIRIS. Stopping ULTOMIRIS may cause breakdown of your red blood cells due to PNH. Symptoms or problems that can happen due to red blood cell breakdown include:. drop in your red blood cell count. tiredness. blood in your urine. stomach-area (abdomen) pain. shortness of breath. blood clots. trouble swallowing. erectile dysfunction (ED) in males. If you have aHUS, your doctor will need to monitor you closely for at least 12 months after stopping treatment for signs of worsening aHUS or problems related to type of abnormal clotting and breakdown of your red blood cells called thrombotic microangiopathy (TMA). Symptoms or problems that can happen with TMA may include:. confusion or loss of consciousness. seizures. chest pain (angina). difficulty breathing. blood clots or stroke. See What is the most important information should know about ULTOMIRIS Infusion-related reactions. Infusion-related reactions may happen during your ULTOMIRIS infusion. Symptoms of an infusion-related reaction with ULTOMIRIS may include lower back pain, feeling faint, or discomfort in your arms or legs. Tell your doctor or nurse right away if you develop these symptoms, or any other symptoms during your ULTOMIRIS infusion that may mean you are having serious infusion reaction, including:chest paintrouble breathing or shortness of breathswelling of your face, tongue, or throatfeel faint or pass out chest pain. trouble breathing or shortness of breath. swelling of your face, tongue, or throat. feel faint or pass out. upper respiratory tract infection. headache. upper respiratory tract infection. diarrhea. nausea. vomiting. headache. high blood pressure. fever.

SPL UNCLASSIFIED SECTION.

Limitations of Use:ULTOMIRIS is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).

STORAGE AND HANDLING SECTION.

Store ULTOMIRIS vials refrigerated at 2C 8C (36F 46F) in the original carton to protect from light. Do not freeze. Do not shake.Refer to Dosage and Administration (2) for information on the stability and storage of diluted solutions of ULTOMIRIS.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no available data on ULTOMIRIS use in pregnant women to inform drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated PNH and aHUS in pregnancy (see Clinical Considerations ). Animal studies using mouse analogue of the ravulizumab-cwvz molecule (murine anti-C5 antibody) showed increased rates of developmental abnormalities and an increased rate of dead and moribund offspring at doses 0.8-2.2 times the human dose (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Clinical Considerations. Disease-associated maternal and/or fetal/neonatal riskPNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages, and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery.In pregnancy, aHUS is associated with adverse maternal outcomes, including preeclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including intrauterine growth restriction (IUGR), fetal death and low birth weight.. Data. Animal DataAnimal reproduction studies were conducted in mice using doses of murine anti-C5 antibody that approximated 1-2.2 times (loading dose) and 0.8-1.8 times (maintenance dose) the recommended human ULTOMIRIS dose, based on body weight comparison. When animal exposure to the antibody occurred in the time period from before mating until early gestation, no decrease in fertility or reproductive performance was observed. When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death. When maternal exposure to the antibody occurred in the time period from implantation through weaning, higher number of male offspring became moribund or died (1/25 controls, 2/25 low dose group, 5/25 high dose group). Surviving offspring had normal development and reproductive function. Human IgG are known to cross the human placental barrier, and thus ULTOMIRIS may potentially cause terminal complement inhibition in fetal circulation.. 8.2 Lactation. Risk summaryThere are no data on the presence of ravulizumab-cwvz in human milk, the effect on the breastfed child, or the effect on milk production. Since many medicinal products and immunoglobulins are secreted into human milk, and because of the potential for serious adverse reactions in nursing child, breastfeeding should be discontinued during treatment and for months after the final dose.. 8.4 Pediatric Use. The safety and effectiveness of ULTOMIRIS for the treatment of PNH have been established in pediatric patients aged one month and older. Use of ULTOMIRIS for this indication is supported by evidence from adequate and well-controlled trials in adults with additional pharmacokinetic, efficacy and safety data in pediatric patients aged to 17 years [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)]. The safety and efficacy for the treatment of pediatric and adult patients with PNH appear similar. Use of ULTOMIRIS in pediatric patients with PNH aged less than years and body weight <30 kg is based on extrapolation of pharmacokinetic pharmacodynamic (PK/PD), and efficacy and safety data from aHUS and PNH clinical studies [see Clinical Pharmacology (12.3) and Clinical Studies (14)].The safety and effectiveness of ULTOMIRIS for the treatment of aHUS have been established in pediatric patients aged one month and older. Use of ULTOMIRIS for this indication is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic, safety, and efficacy data in pediatric patients aged 10 months to <17 years. The safety and efficacy of ULTOMIRIS for the treatment of aHUS appear similar in pediatric and adult patients [see Adverse Reactions (6.1), and Clinical Studies (14.2)].. 8.5 Geriatric Use. Clinical studies of ULTOMIRIS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Other Infections: Use caution when administering ULTOMIRIS to patients with any other systemic infection (5.2).Infusion-Related Reactions: Monitor patients during infusion, interrupt for reactions, and institute appropriate supportive measures (5.5).. Other Infections: Use caution when administering ULTOMIRIS to patients with any other systemic infection (5.2).. Infusion-Related Reactions: Monitor patients during infusion, interrupt for reactions, and institute appropriate supportive measures (5.5).. 5.1Serious Meningococcal Infections. Risk and PreventionLife-threatening meningococcal infections have occurred in patients treated with ULTOMIRIS. The use of ULTOMIRIS increases patients susceptibility to serious meningococcal infections (septicemia and/or meningitis). Meningococcal disease due to any serogroup may occur.Vaccinate for meningococcal disease according to the most current Advisory Committee on Immunization Practices (ACIP) recommendations for patients with complement deficiencies. Revaccinate patients in accordance with ACIP recommendations considering the duration of ULTOMIRIS therapy.Immunize patients without history of meningococcal vaccination at least weeks prior to receiving the first dose of ULTOMIRIS. If urgent ULTOMIRIS therapy is indicated in an unvaccinated patient, administer meningococcal vaccine(s) as soon as possible and provide patients with weeks of antibacterial drug prophylaxis.In clinical studies, 59 adult patients with PNH were treated with ULTOMIRIS less than weeks after meningococcal vaccination. All of these patients received antibiotics for prophylaxis of meningococcal infection until at least weeks after meningococcal vaccination. The benefits and risks of antibiotic prophylaxis for prevention of meningococcal infections in patients receiving ULTOMIRIS have not been established.Vaccination reduces, but does not eliminate, the risk of meningococcal infections. In PNH clinical studies in adult patients, out of 261 PNH patients developed serious meningococcal infections/sepsis while receiving treatment with ULTOMIRIS; all had been vaccinated. These patients recovered while continuing treatment with ULTOMIRIS. In the PNH study in pediatric patients, no meningococcal infections occurred among the 13 patients receiving treatment with ULTOMIRIS.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 steps to be taken to seek immediate medical care. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider discontinuation of ULTOMIRIS in patients who are undergoing treatment for serious meningococcal infection.. REMSDue to the risk of meningococcal infections, ULTOMIRIS is available only through restricted program under Risk Evaluation and Mitigation Strategy (REMS). Under the ULTOMIRIS REMS, prescribers must enroll in the program.Prescribers must counsel patients about the risk of meningococcal infection/sepsis, provide the patients with the REMS educational materials, and ensure patients are vaccinated with meningococcal vaccines.Enrollment in the ULTOMIRIS REMS and additional information are available by telephone: 1-888-765-4747 or at www.ultomirisrems.com.. 5.2Other Infections. ULTOMIRIS blocks terminal complement activation; therefore, patients may have increased susceptibility to encapsulated bacteria infections, especially infections caused by Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and to 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 (Hib). Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type (Hib) infections according to ACIP guidelines. If ULTOMIRIS therapy is administered to patients with active systemic infections, monitor closely for signs and symptoms of worsening infection.. 5.3Monitoring Disease Manifestations after ULTOMIRIS Discontinuation. Treatment Discontinuation for PNHAfter discontinuing treatment with ULTOMIRIS, closely monitor for signs and symptoms of hemolysis, identified by elevated 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 aHUSULTOMIRIS treatment of aHUS should be minimum duration of months. Due to heterogeneous nature of aHUS events and patient-specific risk factors, treatment duration beyond the initial 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 second measurement 28 days apart with no interruptiona 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.. 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 second measurement 28 days apart with no interruptiona 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. 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.. 5.4 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.. 5.5 Infusion-Related Reactions. Administration of ULTOMIRIS may result in infusion-related reactions including anaphylaxis [see Postmarketing Experience (6.3)] and hypersensitivity reactions. In clinical trials, out of 309 patients treated with ULTOMIRIS experienced infusion-related reactions (lower back pain, drop in blood pressure, elevation in blood pressure and limb discomfort) during ULTOMIRIS administration. These reactions did not require discontinuation of ULTOMIRIS. Interrupt ULTOMIRIS infusion and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Plasma Exchange, Plasmapheresis, or Intravenous Immunoglobulins: concomitant use requires supplemental dose of ULTOMIRIS (7.1).Neonatal Fc Receptor Blockers: Closely monitor for reduced effectiveness of ULTOMIRIS (7.2).. Plasma Exchange, Plasmapheresis, or Intravenous Immunoglobulins: concomitant use requires supplemental dose of ULTOMIRIS (7.1).. Neonatal Fc Receptor Blockers: Closely monitor for reduced effectiveness of ULTOMIRIS (7.2).. 7.1Plasma 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 supplemental dose of ULTOMIRIS [see Dosage and Administration (2.3)]. 7.2Neonatal 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.

INSTRUCTIONS FOR USE SECTION.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.Issued: 07/2022 INSTRUCTIONS FOR USE On-Body Delivery System for ULTOMIRIS(R) (uhl-toh-mee-ris) (ravulizumab-cwvz) injection for subcutaneous useSingle-Use, On-Body Injector and 245 mg/3.5 mL Prefilled CartridgeThis Instructions for Use contains information on how to inject ULTOMIRIS subcutaneously using an on-body delivery system.Read this Instructions for Use prior to each use of the ULTOMIRIS on-body injector and prefilled cartridge as there may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. See the Medication Guide that comes with ULTOMIRIS for important information.Important Information You Need to Know Before Injecting ULTOMIRIS SubcutaneouslyIt is important that you receive training from your healthcare provider on how to inject ULTOMIRIS before giving an injection.If you have serious allergic reaction (such as chest pain, trouble breathing, facial swelling, and/or feeling faint), remove the on-body injector(s) to stop the injection and get medical help right away. You will need ULTOMIRIS on-body injectors and prefilled cartridges to receive your full dose.1 Full Dose of ULTOMIRIS 2 ULTOMIRIS On-Body Injectors and Prefilled Cartridges each weekGuide to PartsPrefilled cartridge (Also referred to as Cartridge)On-Body Injector (Also referred to as Injector)Important: Needle is inside.ImportantStoring your ULTOMIRIS on-body injector and prefilled cartridge:Store ULTOMIRIS injector and cartridge in the refrigerator between 36F to 46F (2C to 8C).Keep the injector and cartridge in the original carton to protect from light or physical damage.For your injection, take injectors and cartridges out of the refrigerator and let them sit at room temperature for at least 45 minutes before you inject.Do not return to the refrigerator. The injector and cartridge may be stored in the original carton box at room temperature between 68F to 77F (20C to 25C) for up to days. Discard (throw away) after days if unused.Do not freeze.Keep ULTOMIRIS and all medicines out of the reach of children.Using your ULTOMIRIS on-body injector and prefilled cartridge:Do not shake or drop the injector or cartridge.Do not remove the injector or cartridge from the carton or clear tray until you are ready to inject.Do not press the blue start button on the injector until you place the loaded injector onto your skin and are ready to inject.After you insert the cartridge into the injector, make sure you inject within minutes. Loading the cartridge more than minutes before your injection can dry out the medicine.Do not use the injector or cartridge if the packaging appears to be opened, or if the injector or cartridge has been dropped or appears to be broken or damaged. Part of the on-body injector or prefilled cartridge may be broken even if you cannot see the damage.Do not reuse the on-body injector and prefilled cartridge. They are single-use only. Do not let the injector get wet from water or other liquids. It contains electronic parts that should not get wet.Keep the on-body injector minimum of inches (10 cm) away from other electronics such as cellular phones.Do not use the injector or cartridge past the expiration date printed on the carton and cartridge.Step 1: Prepare1ARemove ULTOMIRIS on-body delivery system cartons from the refrigerator. You will need to use injectors and cartridges for full dose. (See Figure A)1BWait at least 45 minutes.Important: Wait at least 45 minutes for the injectors and cartridges in the cartons to naturally reach room temperature. (See Figure B)Do not use microwave, hot water, hair dryer, or any other heat sources to warm the prefilled cartridge.Do not return to the refrigerator. The injectors and cartridges may be stored in the original carton box at room temperature between 68F to 77F (20C to 25C) for up to days. Throw away (discard) after days if unused.See the Frequently Asked Questions section for additional information on returning the on-body injector and prefilled cartridge to the refrigerator.1COpen the cartons and peel away the white paper covers (See Figure C). Remove the plastic covers from the clear trays using the finger hole (See Figure D).Leave the injectors and cartridges in the trays until ready to use.Do not touch the blue start button until the injectors are on your skin and you are ready to inject.Do not use if the white paper cover(s) or plastic cover(s) is missing or damaged. If either is missing, call 1-888-765-4747.1DGather all supplies needed for your injection and then wash your hands with soap and water. You can also wear gloves.On clean, well-lit work surface, place the:2 clear trays containing the on-body injectors and prefilled cartridges (See Figure E)Additional supplies (See Figure F):Alcohol wipesCotton ball or gauze padAdhesive bandageSharps disposal container1EPrepare and clean different injection sites. Wipe both injection sites with new alcohol wipe and let your skin air dry. (See Figure G)The sites you may choose are:Do not inject into areas of the skin that are tender, bruised, red or hard, or areas with wrinkles, skin folds, scars, tattoos, stretch marks, moles, or excessive hair.Do not use the same sites weeks in row. Change (rotate) your injection sites every week to reduce irritation.REPEAT Steps 2A 3C for each injectionStep 2: Get Ready2ASwing open the blue cartridge door (See Figure H). Leave the door open. Do not close the cartridge door before the cartridge is loaded.The door should not be closed when removed from the package. If the door is closed, press firmly on the ribbed side of the door and swing the door to open. (See Figure I)2BInspect the cartridge. (See Figure J)Check the expiration date. Do not use the cartridge if the expiration date has passed.Check the medicine in the cartridge. The medicine should be clear and colorless to slightly yellow in color.Do not use if the medicine is cloudy, discolored, or contains flakes or particles.Do not use if any part of cartridge looks cracked, broken, or if pieces are missing.In any of the above cases, use new on-body injector and prefilled cartridge and contact 1-888-765-4747.2CClean the cartridge bottom with new alcohol wipe. (See Figure K)With hand, hold the prefilled cartridge barrel in the middle.Do not hold it by the ends.Do not turn (rotate) or remove the top or bottom of the cartridge.Do not touch the cartridge bottom after cleaning.2DLoad the cleaned cartridge into the injector and gently press on the top until it is secured in place. (See Figure L)Insert the cartridge into the injector with the arrow pointing down (bottom first).Note: It is okay to see few drops of the medicine coming out of the needle.Important: Do not insert the cartridge more than minutes before your injection. This can dry out the medicine. See the Frequently Asked Questions section for more information.2EClose the cartridge door. Squeeze it firmly until it snaps shut and there are no gaps between the injector and the cartridge door. (See Figure M)Do not re-open door or remove the cartridge.Do not touch the blue start button until you have placed the injector onto your skin or the injector will not work. Important: Go to the next step right away after loading the cartridge and closing the door.Step 3: Inject3APeel away both green pull tabs to show adhesive. (See Figure N)The Injector will turn on when the smaller pull tab is removed (along with battery strip).You will hear beeps repeating every 30 seconds until the blue button is pressed.The status light will begin to flash blue.Do not pull the skin adhesive backing off of the injector.Do not touch the skin adhesive.Do not touch the start button until you have placed the loaded injector onto your skin.To prevent injury, do not touch the needle cover area.Do not place the loaded injector on your body if the red status light flashes continuously.Do not fold the skin adhesive over onto itself.3BStick the injector onto the clean, dry, chosen injection site(s). (See Figure O)Place the injector so that:You can see the status light.The injectors are at least inch (2.5 cm) apart.Clothing is kept away from adhesive.Firmly press the injector onto the skin.Run your finger around the adhesive edges to make sure the adhesive is secure.Do not move the loaded injector after it has been placed onto your skin.Important: If placing on stomach, stretch any loose skin as shown with hand. Standing up may make this easier.3CFirmly press and release the blue start button on the injector to start the injection. (See Figure P)You will hear beeps when the blue button is pressed and injection starts.The status light will flash green during the injection.The sound of the injector motor will be heard for about 10 minutes during the injection.You may feel pinch.Light physical activities can be done during injection, such as walking, reaching, and bending.The injector should stay dry. Do not let the injector get wet from water or other liquids. It contains electronic parts that should not get wet.Important: If you have serious allergic reaction (such as chest pain, trouble breathing, facial swelling, and/or feeling faint), remove the injector(s) to stop the injection and get medical help right away. 3DREPEAT Steps 2A 3C with the second injector.You must use injectors to receive full dose.When the second injector is activated, continue to Step 4.Step 4: Monitor4AMonitor both injectors until they are complete. Each injection takes about 10 minutes to finish. (See Figure Q)The Injection is complete when each injector:Status light turns solid green.Begins beeping times every 30 seconds.White plunger fills the medicine window. (See Figure Q)Step 5: Removal and Disposal5ARemove the injectors after both injections are complete. Grip the adhesive and peel the injectors off your skin. (See Figure R)The green status light will turn off when the injector is removed from your skin. The injector will beep times and then stop making noise.5BDispose of (throw away) the used ULTOMIRIS on-body injectors and prefilled cartridges. (See Figure S)Put the used ULTOMIRIS on-body injectors and prefilled cartridges in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the ULTOMIRIS on-body injectors and prefilled cartridges in your household trash.If you do not have an FDA-cleared sharps disposal container, you may use household container that is:- made of heavy-duty plastic,- can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,- upright and stable during use,- leak-resistant, and- properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposalDo not recycle your used sharps disposal container.5CCheck the injection sites.If there is blood at the injection sites, press cotton ball or gauze pad on site.Apply an adhesive bandage if necessary.Do not rub the injection site.TroubleshootingWhat do do if the loaded on-body injector status light flashes red and hear beepsImportant: If the status light turns red, injector leaks, or either injector does not complete injection, remove and call 1-888-765-4747 immediately (See Figure T).A red status light indicates that the injector will not work.Frequently Asked QuestionsHow many on-body injectors do need for full doseYou need on-body injectors and prefilled cartridges for full weekly dose. You may prepare and use on-body injectors and prefilled cartridges at the same time.What happens if the status light flashes red and hear beepsIf the status light flashes red at any time, this means there is an error and the on-body injector will no longer work. Remove the on-body injector from the body (if it is attached) and place it in the original packaging. Do not remove the prefilled cartridge from the on-body injector. Contact 1-888-765-4747 and return the on-body injector and cartridge per the instructions given.I cannot open the blue cartridge door. How do open itSee Step 2A and Figure I. If you still cannot open it, contact 1-888-765-4747.What if the on-body injector does not beep and the blue status light does not blink when remove the pull tabsFirst check that both pull tabs on the back of the on-body injector have been fully removed, including the battery strip. If the on-body injector still does not turn on, use new on-body injector and prefilled cartridge. Contact 1-888-765-4747.What if push the blue start button before stick the on-body injector on the skinIf you removed the pull tabs and pressed the start button, the on-body injector will make beeping sound and you will see the status light flash red. The on-body injector will no longer work. Stop using the on-body injector and contact 1-888-765-4747.What if the on-body injector is already on the skin but does not start after pressing the blue start buttonMake sure you firmly press the blue start button. If it still does not start, remove the on-body injector and contact 1-888-765-4747. Do not reapply the same on-body injector as it will not work. Use new on-body injector and prefilled cartridge.What if part of the packaging is missing or damaged (for example: carton, paper cover, plastic cover, etc.)Do not use the on-body injector or prefilled cartridge and contact 1-888-765-4747.What happens if do not inject within minutes after loading the prefilled cartridgeIt is important to inject within minutes after loading the prefilled cartridge.After you load the prefilled cartridge into the on-body injector, it is completely normal to see the medicine drop out of the needle. This is to get rid of the air from the on-body injector needle. However, if you wait more than minutes to start your injection, you may lose some of your medicine. Additionally, this may dry out the medicine and clog the on-body injector needle.If am not ready to inject after waiting at least 45 minutes, can return the on-body injector and prefilled cartridge to the refrigeratorDo not return to the refrigerator the on-body injectors and prefilled cartridges after they reach room temperature. This may degrade the medicine. If needed, the on-body injectors and prefilled cartridges may be stored in the original carton box at room temperature between 68F to 77F (20C to 25C) for up to days. Throw away after days if unused.For any additional questions or support, contact 1-888-765-4747. Additional Environmental ConditionsRelative humidity range is 15% to 85%.Altitude range is -984 feet to 11483 feet (-300 meters to 3500 meters).During injection, keep the on-body injector minimum of inches (10 cm) away from other electronics such as cellular phones.Warning: Do not modify the on-body injector or prefilled cartridge.Warning: Magnetic Resonance (MR) is unsafe, the on-body injector for ULTOMIRIS should not enter the MR scanning room.On-body injector operating temperature range is 59F to 104F (15C to 40C).Symbol Table Refer to Instructions for UseDo not use if packaging is damagedKeep DrySingle UseType BF Applied PartSterilized using ethylene oxideCautionUse-By DateBatch CodeCatalogue NumberULTOMIRIS On-Body Delivery SystemOpen HereSerial NumberMR Unsafe Manufactured by:Alexion Pharmaceuticals, Inc.Boston, MA 02210 USAU.S. License No. 1743ULTOMIRIS is trademark of Alexion Pharmaceuticals, Inc.(C) 2022 Alexion Pharmaceuticals, Inc.. It is important that you receive training from your healthcare provider on how to inject ULTOMIRIS before giving an injection.. If you have serious allergic reaction (such as chest pain, trouble breathing, facial swelling, and/or feeling faint), remove the on-body injector(s) to stop the injection and get medical help right away. You will need ULTOMIRIS on-body injectors and prefilled cartridges to receive your full dose.. Store ULTOMIRIS injector and cartridge in the refrigerator between 36F to 46F (2C to 8C).. Keep the injector and cartridge in the original carton to protect from light or physical damage.. For your injection, take injectors and cartridges out of the refrigerator and let them sit at room temperature for at least 45 minutes before you inject.. Do not return to the refrigerator. The injector and cartridge may be stored in the original carton box at room temperature between 68F to 77F (20C to 25C) for up to days. Discard (throw away) after days if unused.. Do not freeze.. Keep ULTOMIRIS and all medicines out of the reach of children.. Do not shake or drop the injector or cartridge.. Do not remove the injector or cartridge from the carton or clear tray until you are ready to inject.. Do not press the blue start button on the injector until you place the loaded injector onto your skin and are ready to inject.. After you insert the cartridge into the injector, make sure you inject within minutes. Loading the cartridge more than minutes before your injection can dry out the medicine.. Do not use the injector or cartridge if the packaging appears to be opened, or if the injector or cartridge has been dropped or appears to be broken or damaged. Part of the on-body injector or prefilled cartridge may be broken even if you cannot see the damage.. Do not reuse the on-body injector and prefilled cartridge. They are single-use only. Do not let the injector get wet from water or other liquids. It contains electronic parts that should not get wet.. Keep the on-body injector minimum of inches (10 cm) away from other electronics such as cellular phones.. Do not use the injector or cartridge past the expiration date printed on the carton and cartridge.. Do not use microwave, hot water, hair dryer, or any other heat sources to warm the prefilled cartridge.. Do not return to the refrigerator. The injectors and cartridges may be stored in the original carton box at room temperature between 68F to 77F (20C to 25C) for up to days. Throw away (discard) after days if unused.. Do not touch the blue start button until the injectors are on your skin and you are ready to inject.. Do not use if the white paper cover(s) or plastic cover(s) is missing or damaged. If either is missing, call 1-888-765-4747.. clear trays containing the on-body injectors and prefilled cartridges (See Figure E). Alcohol wipes. Cotton ball or gauze pad. Adhesive bandage. Sharps disposal container. Do not inject into areas of the skin that are tender, bruised, red or hard, or areas with wrinkles, skin folds, scars, tattoos, stretch marks, moles, or excessive hair.. Do not use the same sites weeks in row. Change (rotate) your injection sites every week to reduce irritation.. Do not use if the medicine is cloudy, discolored, or contains flakes or particles.. Do not use if any part of cartridge looks cracked, broken, or if pieces are missing.. Do not hold it by the ends.. Do not turn (rotate) or remove the top or bottom of the cartridge.. Do not touch the cartridge bottom after cleaning.. Note: It is okay to see few drops of the medicine coming out of the needle.. Do not pull the skin adhesive backing off of the injector.. Do not touch the skin adhesive.. Do not touch the start button until you have placed the loaded injector onto your skin.. To prevent injury, do not touch the needle cover area.. Do not place the loaded injector on your body if the red status light flashes continuously.. Do not fold the skin adhesive over onto itself.. You can see the status light.. The injectors are at least inch (2.5 cm) apart.. Clothing is kept away from adhesive.. Do not move the loaded injector after it has been placed onto your skin.. You will hear beeps when the blue button is pressed and injection starts.. The status light will flash green during the injection.. The sound of the injector motor will be heard for about 10 minutes during the injection.. You may feel pinch.. Light physical activities can be done during injection, such as walking, reaching, and bending.. The injector should stay dry. Do not let the injector get wet from water or other liquids. It contains electronic parts that should not get wet.. Status light turns solid green.. Begins beeping times every 30 seconds.. White plunger fills the medicine window. (See Figure Q). Put the used ULTOMIRIS on-body injectors and prefilled cartridges in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the ULTOMIRIS on-body injectors and prefilled cartridges in your household trash.. If you do not have an FDA-cleared sharps disposal container, you may use household container that is:- made of heavy-duty plastic,- can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,- upright and stable during use,- leak-resistant, and- properly labeled to warn of hazardous waste inside the container. - made of heavy-duty plastic,. can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,. upright and stable during use,. leak-resistant, and. properly labeled to warn of hazardous waste inside the container.. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal. Do not recycle your used sharps disposal container.. If there is blood at the injection sites, press cotton ball or gauze pad on site.. Apply an adhesive bandage if necessary.. Do not rub the injection site.. You need on-body injectors and prefilled cartridges for full weekly dose. You may prepare and use on-body injectors and prefilled cartridges at the same time.. If the status light flashes red at any time, this means there is an error and the on-body injector will no longer work. Remove the on-body injector from the body (if it is attached) and place it in the original packaging. Do not remove the prefilled cartridge from the on-body injector. Contact 1-888-765-4747 and return the on-body injector and cartridge per the instructions given.. See Step 2A and Figure I. If you still cannot open it, contact 1-888-765-4747.. First check that both pull tabs on the back of the on-body injector have been fully removed, including the battery strip. If the on-body injector still does not turn on, use new on-body injector and prefilled cartridge. Contact 1-888-765-4747.. If you removed the pull tabs and pressed the start button, the on-body injector will make beeping sound and you will see the status light flash red. The on-body injector will no longer work. Stop using the on-body injector and contact 1-888-765-4747.. Make sure you firmly press the blue start button. If it still does not start, remove the on-body injector and contact 1-888-765-4747. Do not reapply the same on-body injector as it will not work. Use new on-body injector and prefilled cartridge.. Do not use the on-body injector or prefilled cartridge and contact 1-888-765-4747.. It is important to inject within minutes after loading the prefilled cartridge.. After you load the prefilled cartridge into the on-body injector, it is completely normal to see the medicine drop out of the needle. This is to get rid of the air from the on-body injector needle. However, if you wait more than minutes to start your injection, you may lose some of your medicine. Additionally, this may dry out the medicine and clog the on-body injector needle.. Do not return to the refrigerator the on-body injectors and prefilled cartridges after they reach room temperature. This may degrade the medicine. If needed, the on-body injectors and prefilled cartridges may be stored in the original carton box at room temperature between 68F to 77F (20C to 25C) for up to days. Throw away after days if unused.. Relative humidity range is 15% to 85%.. Altitude range is -984 feet to 11483 feet (-300 meters to 3500 meters).. During injection, keep the on-body injector minimum of inches (10 cm) away from other electronics such as cellular phones.. Warning: Do not modify the on-body injector or prefilled cartridge.. Warning: Magnetic Resonance (MR) is unsafe, the on-body injector for ULTOMIRIS should not enter the MR scanning room.. On-body injector operating temperature range is 59F to 104F (15C to 40C).. Figure. Figure. Figure. Figure. Figure A. Figure B. Figure C. Figure D. Figure E. Figure F. Figure G. Figure H. Figure I. Figure J. Figure K. Figure L. Figure. Figure N. Figure O. Figure P. Figure. Figure Q. Figure. Figure R. Figure S. Figure T. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure.