ULTOMIRIS SIDE EFFECTS
- Generic Name: ravulizumab-cwvz injection
- Brand Name: Ultomiris
- Drug Class: Monoclonal Antibodies
SIDE EFFECTS
The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:
- Serious Meningococcal Infections
- Other Infections
- Infusion-Related Reactions
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Adult Population With PNH
The data described below reflect exposure of 441 adult patients with PNH in Phase 3 studies who received ULTOMIRIS (n = 222) or eculizumab (n = 219) at the recommended dosing regimens with median treatment duration of 6 months for ULTOMIRIS and 6 months for eculizumab. The most frequent adverse reactions (≥10%) with ULTOMIRIS were upper respiratory tract infection and headache. Table 9 describes adverse reactions that occurred at a rate of 5% or more among patients treated with ULTOMIRIS in PNH studies.
Serious adverse reactions were reported in 15 (6.8%) patients with PNH receiving ULTOMIRIS. The serious adverse reactions in patients treated with ULTOMIRIS included hyperthermia and pyrexia. No serious adverse reaction was reported in more than 1 patient treated with ULTOMIRIS.
One fatal case of sepsis was identified in a patient treated with ULTOMIRIS.
Table 1: Adverse Reactions Reported in 5% or More of ULTOMIRIS-Treated Patients in Complement Inhibitor Naive and Eculizumab- Experienced Adult Patients with PNH
| Body System Adverse Reaction |
Number of Patients | |
| ULTOMIRIS (N=222) n (%) |
Eculizumab (N=219) n (%) |
|
| Gastrointestinal disorders | ||
| Diarrhea | 19 (9) | 12 (5) |
| Nausea | 19 (9) | 19 (9) |
| Abdominal pain | 13 (6) | 16 (7) |
| General Disorders and Administration Site Conditions | ||
| Pyrexia | 15 (7) | 18 (8) |
| Infections and Infestations | ||
| Upper respiratory tract infectiona | 86 (39) | 86 (39) |
| Musculoskeletal and Connective Tissue Disorders | ||
| Pain in extremity | 14 (6) | 11 (5) |
| Arthralgia | 11 (5) | 12 (5) |
| Nervous System Disorders | ||
| Headache | 71 (32) | 57 (26) |
| Dizziness | 12 (5) | 14 (6) |
| a Grouped term includes: nasopharyngitis, upper respiratory tract infection, oropharyngeal pain, viral upper respiratory tract infection, rhinitis, respiratory tract infection, rhinorrhea, pharyngitis, and upper respiratory tract inflammatio | ||
Clinically relevant adverse reactions in 1% of patients include infusion-related reactions.
Pediatric Population With PNH
In pediatric patients with PNH (aged 9 to 17 years old) included in the pediatric PNH Phase 3 study, the safety profile appeared similar to that observed in adult patients with PNH and in pediatric and adult patients with aHUS. The most common adverse reactions (>20%) were upper respiratory tract infection, anemia, abdominal pain, and headache. Table 2 describes the adverse reactions that occurred at a rate of 10% or more among pediatric patients treated with ULTOMIRIS in Study ALXN1210-PNH-304.
Table 2: Adverse Reactions Reported in 10% or More of ULTOMIRISTreated Pediatric Patients with PNH in Study ALXN1210-PNH-304
| Body System Adverse Reaction |
Treatment Naive (N=5) |
Eculizumab Experienced (N=8) |
Total (N=13) |
| n (%) | n (%) | n (%) | |
| Blood and lymphatic system disorders | |||
| Anemiaa | 1 (20) | 2 (25) | 3 (23) |
| Gastrointestinal disorders | |||
| Abdominal pain | 0 (0) | 3 (38) | 3 (23) |
| Constipation | 0 (0) | 2 (25) | 2 (15) |
| General disorders and administration site conditions | |||
| Pyrexia | 1 (20) | 1 (13) | 2 (15) |
| Infections and infestations | |||
| Upper Respiratory tract infectionb | 1 (20) | 6 (75) | 7 (54) |
| Musculoskeletal and connective tissue disorders | |||
| Pain in extremity | 0 (0) | 2 (25) | 2 (15) |
| Nervous system disorders | |||
| Headache | 1 (20) | 2 (25) | 3 (23) |
| a Grouped term includes: anemia and iron deficiency anemia b Grouped term includes: nasopharyngitis, upper respiratory tract infection, oropharyngeal pain and viral upper respiratory tract infection |
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Atypical Hemolytic Uremic Syndrome (aHUS)
The data described below reflect exposure of 58 adult and 16 pediatric patients with aHUS in single-arm trials who received ULTOMIRIS at the recommended dose and schedule. The most frequent adverse reactions reported in ≥20% of patients treated with ULTOMIRIS were upper respiratory tract infection, diarrhea, nausea, vomiting, headache, hypertension, and pyrexia. Table 11, Table 12, and Table 13 describe adverse reactions that occurred at a rate of 10% or more among patients treated with ULTOMIRIS in aHUS studies. Serious adverse reactions were reported in 42 (57%) patients with aHUS receiving ULTOMIRIS. The most frequent serious adverse reactions reported in more than 2 patients (2.7%) treated with ULTOMIRIS were hypertension, pneumonia and abdominal pain. Four patients died during the ALXN1210-aHUS-311 study. The cause of death was sepsis in two patients and intracranial hemorrhage in one patient. The fourth patient, who was excluded from the trial after a diagnosis of STECHUS, died due to pretreatment cerebral arterial thrombosis.
Table 3: Adverse Reactions Reported in ≥10% of ULTOMIRIS-Treated Patients with aHUS in Study ALXN1210-aHUS-311
| Body System Adverse Reaction |
ALXN1210-aHUS-311 (N=58) | |
| All Grades*** (n=53) n (%) |
≥ Grade 3 (n=14) n (%) |
|
| Blood and lymphatic system disorders | ||
| Anemia | 8 (14) | 0 (0) |
| Gastrointestinal disorders | ||
| Diarrhea | 18 (31) | 2 (3) |
| Nausea | 15 (26) | 2 (3) |
| Vomiting | 15 (26) | 2 (3) |
| Constipation | 8 (14) | 1 (2) |
| Abdominal pain | 7 (12) | 1 (2) |
| General disorders and administration site conditions | ||
| Pyrexia | 11 (19) | 1 (2) |
| Edema peripheral | 10 (17) | 0 (0) |
| Fatigue | 8 (14) | 0 (0) |
| Infections and infestations | ||
| Upper respiratory tract infection* | 15 (26) | 0 (0) |
| Urinary tract infection | 10 (17) | 5 (9) |
| Gastrointestinal infection** | 8 (14) | 2 (3) |
| Metabolism and nutrition disorders | ||
| Hypokalemia | 6 (10) | 1 (2) |
| Musculoskeletal and connective tissue disorders | ||
| Arthralgia | 13 (22) | 0 (0) |
| Back pain | 7 (12) | 1 (2) |
| Muscle spasms | 6 (10) | 0 (0) |
| Pain in extremity | 6 (10) | 0 (0) |
| Nervous system disorders | ||
| Headache | 23 (40) | 1 (2) |
| Psychiatric disorders | ||
| Anxiety | 8 (14) | 1 (2) |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough | 10 (17) | 0 (0) |
| Dyspnea | 10 (17) | 1 (2) |
| Skin and subcutaneous tissue disorders | ||
| Alopecia | 6 (10) | 0 (0) |
| Dry skin | 6 (10) | 0 (0) |
| Vascular disorders | ||
| Hypertension | 14 (24) | 7 (12) |
| *: Grouped term includes nasopharyngitis, pharyngitis, upper respiratory tract infection, rhinitis, viral upper respiratory tract infection, rhinovirus infection, viral pharyngitis, rhinorrhea, and oropharyngeal pain. **: Grouped term includes gastroenteritis, gastrointestinal infection, enterocolitis infectious, infectious colitis, and enterocolitis. ***: Graded per CTCAE v5.0. |
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Clinically relevant adverse reactions include viral tonsilitis (in <10% of patients) and infusion-related reactions (in 3% of patients).
Table 4: Adverse Reactions Reported in ≥10% of ULTOMIRIS-Treated Patients with aHUS in Study ALXN1210-aHUS-312
| Body System Adverse Reaction |
ALXN1210-aHUS-312 (N=16) | |
| All Grades** (n=16) n (%) |
≥ Grade 3 (n=6) n (%) |
|
| Blood and lymphatic system disorders | ||
| Anemia | 2 (13) | 1 (6) |
| Lymphadenopathy | 2 (13) | 0 (0) |
| Gastrointestinal disorders | ||
| Diarrhea | 6 (38) | 0 (0) |
| Constipation | 4 (25) | 0 (0) |
| Vomiting | 4 (25) | 1 (6) |
| Abdominal pain | 3 (19) | 0 (0) |
| Nausea | 2 (13) | 0 (0) |
| General disorders and administration site conditions | ||
| Pyrexia | 8 (50) | 0 (0) |
| Infections and infestations | ||
| Upper respiratory tract infection* | 7 (44) | 1 (6) |
| Gastroenteritis viral | 2 (13) | 2 (13) |
| Pneumonia | 2 (13) | 1 (6) |
| Tonsillitis | 2 (13) | 0 (0) |
| Injury, poisoning and procedural complications | ||
| Contusion | 3 (19) | 0 (0) |
| Investigations | ||
| Vitamin D decreased | 3 (19) | 0 (0) |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 2 (13) | 0 (0) |
| Iron deficiency | 2 (13) | 0 (0) |
| Musculoskeletal and connective tissue disorders | ||
| Myalgia | 3 (19) | 0 (0) |
| Pain in extremity | 2 (13) | 0 (0) |
| Nervous system disorders | ||
| Headache | 5 (31) | 0 (0) |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough | 3 (19) | 0 (0) |
| Dyspnea | 2 (13) | 0 (0) |
| Skin and subcutaneous tissue disorders | ||
| Rash | 3 (19) | 0 (0) |
| Vascular disorders | ||
| Hypertension | 4 (25) | 1 (6) |
| Hypotension | 2 (13) | 0 (0) |
| *: Grouped term includes nasopharyngitis, pharyngitis, upper respiratory tract infection, rhinitis, viral upper respiratory tract infection, rhinovirus infection, viral pharyngitis, rhinorrhea, and oropharyngeal pain. **: Graded per CTCAE v5.0. |
||
Clinically relevant adverse reactions in <10% of patients include viral infection.
Table 5: Adverse Reactions Reported in ≥10% of ULTOMIRIS-Treated Patients from Birth to 16 Years of Age with aHUS in Study ALXN1210-aHUS-312
| Body System Adverse Reaction |
ALXN1210-aHUS-312 | |||
| Age 0 to <2 (N=2) |
Age 2 to <12 (N=12) |
Age 12 to 16 (N=1) |
Total (N=15) |
|
| n (%) | n (%) | n (%) | n (%) | |
| Blood and lymphatic system disorders | ||||
| Lymphadenopathy | 0 (0) | 2 (17) | 0 (0) | 2 (13) |
| Gastrointestinal disorders | ||||
| Diarrhea | 1 (50) | 3 (25) | 1 (100) | 5 (33) |
| Constipation | 0 (0) | 4 (33) | 0 (0) | 4 (27) |
| Vomiting | 0 (0) | 3 (25) | 0 (0) | 3 (20) |
| Abdominal pain | 0 (0) | 2 (17) | 0 (0) | 2 (13) |
| General disorders and administration site conditions | ||||
| Pyrexia | 1 (50) | 5 (42) | 1 (100) | 7 (47) |
| Infections and infestations | ||||
| Upper respiratory tract infection* | 1 (50) | 6 (50) | 0 (0) | 7 (47) |
| Gastroenteritis viral | 0 (0) | 2 (17) | 0 (0) | 2 (13) |
| Tonsillitis | 1 (50) | 1 (8) | 0 (0) | 2 (13) |
| Injury, poisoning and procedural complications | ||||
| Contusion | 0 (0) | 2 (17) | 0 (0) | 2 (13) |
| Investigations | ||||
| Vitamin D decreased | 0 (0) | 2 (17) | 1 (100) | 3 (20) |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 1 (50) | 1 (8) | 0 (0) | 2 (13) |
| Iron deficiency | 0 (0) | 2 (17) | 0 (0) | 2 (13) |
| Musculoskeletal and connective tissue disorders | ||||
| Myalgia | 1 (50) | 1 (8) | 0 (0) | 2 (13) |
| Pain in extremity | 0 (0) | 2 (17) | 0 (0) | 2 (13) |
| Nervous system disorders | ||||
| Headache | 0 (0) | 4 (33) | 0 (0) | 4 (27) |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 0 (0) | 3 (25) | 0 (0) | 3 (20) |
| Dyspnea | 1 (50) | 1 (8) | 0 (0) | 2 (13) |
| Skin and subcutaneous tissue disorders | ||||
| Rash | 1 (50) | 2 (17) | 0 (0) | 3 (20) |
| Vascular disorders | ||||
| Hypertension | 1 (50) | 3 (25) | 0 (0) | 4 (27) |
| Hypotension | 0 (0) | 2 (17) | 0 (0) | 2 (13) |
| *: Grouped term includes nasopharyngitis, pharyngitis, upper respiratory tract infection, rhinitis, viral upper respiratory tract infection, rhinovirus infection, viral pharyngitis, rhinorrhea, and oropharyngeal pain | ||||
Clinically relevant adverse reactions in <10% of patients include viral infection.
Generalized Myasthenia Gravis (gMG)
Adult Population With gMG
The safety of ULTOMIRIS has been evaluated in 175 adult patients with gMG, including 169 patients who received at least one dose of ULTOMIRIS, 142 patients who were exposed for at least 6 months, and 95 who were exposed for at least 12 months. In a randomized, double-blind, placebo-controlled trial (ALXN1210-MG-306), the most frequent adverse reactions (≥10%) with ULTOMIRIS were diarrhea and upper respiratory tract infection. Table 14 describes adverse reactions that occurred at a rate of 5% or more and at greater frequency than placebo. Serious adverse reactions were reported in 20 (23%) patients with gMG receiving ULTOMIRIS and in 14 (16%) patients receiving placebo. The most frequent serious adverse reactions were infections reported in at least 8 (9%) patients treated with ULTOMIRIS and in 4 (4%) patients treated with placebo. Of these infections, one fatal case of COVID-19 pneumonia was identified in a patient treated with ULTOMIRIS and one case of infection led to discontinuation of ULTOMIRIS.
Table 6: Adverse Reactions Reported in ≥5% and at Greater Frequency than Placebo in ULTOMIRIS-Treated Adult Patients with gMG in Study ALXN1210-MG-306
| Body System Adverse Reaction |
Number of Patients | |
| ULTOMIRIS (N=86) n (%) |
Placebo (N=89) n (%) |
|
| Gastrointestinal Disorders | ||
| Diarrhea | 13 (15) | 11 (12) |
| Abdominal pain | 5 (6) | 0 |
| Infections and Infestations | ||
| Upper respiratory tract infection | 12 (14) | 7 (8) |
| Urinary tract infection | 5 (6) | 4 (4) |
| Musculoskeletal and Connective Tissue Disorders | ||
| Back Pain | 7 (8) | 5 (6) |
| Nervous System Disorders | ||
| Dizziness | 8 (9) | 3 (3) |
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 ravulizumabcwvz 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 1 of 219 (0.5%) patients with PNH and 1 of 71 (1.4%) patients with aHUS. In these 2 patient populations, no apparent correlation of antibody development to altered pharmacokinetic profile, clinical response, or adverse events was observed.
No treatment-emergent antibodies to ravulizumab-cwvz were detected in patients with gMG treated with ULTOMIRIS.
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.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of ULTOMIRIS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to ULTOMIRIS exposure.
Serious Adverse Reaction: Anaphylaxis
SRC: NLM .