Ultomiris: Package Insert and Label Information (Page 2 of 7)

3 DOSAGE FORMS AND STRENGTHS

ULTOMIRIS 100 mg/mL

Injection: 300 mg/3 mL (100 mg/mL) and 1,100 mg/11 mL (100 mg/mL) as a translucent, clear to yellowish color solution in a single-dose vial.

ULTOMIRIS 10 mg/mL

Injection: 300 mg/30 mL (10 mg/mL) as a clear to translucent, slight whitish color solution in a single-dose vial.

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 a meningococcal infection [see Warnings and Precautions (5.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Serious Meningococcal Infections

Risk and Prevention

Life-threatening meningococcal infections have occurred in patients treated with ULTOMIRIS. The use of ULTOMIRIS increases a patient’s 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 a history of meningococcal vaccination at least 2 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 2 weeks of antibacterial drug prophylaxis.

In clinical studies, 59 adult patients with PNH and 2 adult patients with gMG were treated with ULTOMIRIS less than 2 weeks after meningococcal vaccination. All of these patients received antibiotics for prophylaxis of meningococcal infection until at least 2 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, 3 out of 261 PNH patients developed serious meningococcal infections/sepsis while receiving treatment with ULTOMIRIS; all 3 had been vaccinated. These 3 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.

REMS

Due to the risk of meningococcal infections, ULTOMIRIS is available only through a restricted program under a 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.

5.2 Other Infections

ULTOMIRIS blocks terminal complement activation; therefore, patients may have increased susceptibility to infections, especially with encapsulated bacteria, such as infections caused by Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae. Children treated with ULTOMIRIS may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP guidelines.

If ULTOMIRIS therapy is administered to patients with active systemic infections, monitor closely for signs and symptoms of worsening infection.

5.3 Monitoring Disease Manifestations after ULTOMIRIS Discontinuation

Treatment Discontinuation for PNH

After discontinuing treatment with ULTOMIRIS, closely monitor for signs and symptoms of hemolysis, identified by elevated LDH along with sudden decrease in PNH clone size or hemoglobin, or reappearance of symptoms such as fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction. Monitor any patient who discontinues ULTOMIRIS for at least 16 weeks to detect hemolysis and other reactions. If signs and symptoms of hemolysis occur after discontinuation, including elevated LDH, consider restarting treatment with ULTOMIRIS.

Treatment Discontinuation for aHUS

ULTOMIRIS treatment of aHUS should be a minimum duration of 6 months. Due to heterogeneous nature of aHUS events and patient-specific risk factors, treatment duration beyond the initial 6 months should be individualized.

There are no specific data on ULTOMIRIS discontinuation.

After discontinuing treatment with ULTOMIRIS, patients should be monitored for clinical symptoms and laboratory signs of TMA complications for at least 12 months.

TMA complications post-discontinuation can be identified if any of the following is observed:

  • Clinical symptoms of TMA include changes in mental status, seizures, angina, dyspnea, thrombosis or increasing blood pressure.
  • In addition, at least two of the following laboratory signs observed concurrently and results should be confirmed by a second measurement 28 days apart with no interruption
    • a decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during ULTOMIRIS treatment;
    • an increase in serum creatinine of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment;
    • an increase in serum LDH of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment.

If TMA complications occur after ULTOMIRIS discontinuation, consider reinitiation of ULTOMIRIS treatment or appropriate organ-specific supportive measures.

5.4 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 Adverse Reactions (6.3)] and hypersensitivity reactions. In clinical trials, infusion-related reactions occurred in approximately 1% of patients treated with ULTOMIRIS. These events included lower back pain, drop in blood pressure, elevation in blood pressure, limb discomfort, drug hypersensitivity (allergic reaction), dysgeusia (bad taste), and drowsiness. These reactions did not require discontinuation of ULTOMIRIS. If signs of cardiovascular instability or respiratory compromise occur, interrupt ULTOMIRIS infusion and institute appropriate supportive measures.

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Adult Population with PNH

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 9: Adverse Reactions Reported in 5% or More of ULTOMIRIS-Treated Patients in Complement Inhibitor Naïve and Eculizumab-Experienced Adult Patients with PNH
Body System Adverse Reaction Number of Patients
ULTOMIRIS(N=222)n (%) Eculizumab(N=219)n (%)
*
Grouped term includes: nasopharyngitis, upper respiratory tract infection, oropharyngeal pain, viral upper respiratory tract infection, rhinitis, respiratory tract infection, rhinorrhea, pharyngitis, and upper respiratory tract inflammation
Gastrointestinal disorders
Diarrhea 19 (9) 12 (5)
Nausea 19 (9) 19 (9)
Abdominal pain 13 (6) 16 (7)
General Disorders and Administration Site Conditions
Pyrexia 15 (7) 18 (8)
Infections and Infestations
Upper respiratory tract infection * 86 (39) 86 (39)
Musculoskeletal and Connective Tissue Disorders
Pain in extremity 14 (6) 11 (5)
Arthralgia 11 (5) 12 (5)
Nervous System Disorders
Headache 71 (32) 57 (26)
Dizziness 12 (5) 14 (6)

Clinically relevant adverse reactions in 1% of patients include infusion-related reactions.

Pediatric Population with PNH

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 10 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 10: Adverse Reactions Reported in 10% or More of ULTOMIRIS-Treated Pediatric Patients with PNH in Study ALXN1210-PNH-304
Body System Adverse Reaction Treatment Naïve Eculizumab Experienced Total
(N=5) (N=8) (N=13)
n (%) n (%) n (%)
*
Grouped term includes: anemia and iron deficiency anemia
Grouped term includes: nasopharyngitis, upper respiratory tract infection, oropharyngeal pain and viral upper respiratory tract infection
Blood and lymphatic system disorders
Anemia * 1 (20) 2 (25) 3 (23)
Gastrointestinal disorders
Abdominal pain 0 (0) 3 (38) 3 (23)
Constipation 0 (0) 2 (25) 2 (15)
General disorders and administration site conditions
Pyrexia 1 (20) 1 (13) 2 (15)
Infections and infestations
Upper Respiratory tract infection 1 (20) 6 (75) 7 (54)
Musculoskeletal and connective tissue disorders
Pain in extremity 0 (0) 2 (25) 2 (15)
Nervous system disorders
Headache 1 (20) 2 (25) 3 (23)

Atypical Hemolytic Uremic Syndrome (aHUS)

The data described below reflect exposure of 58 adult and 16 pediatric patients with aHUS in single-arm trials who received ULTOMIRIS at the recommended dose and schedule. The most frequent adverse reactions reported in ≥20% of patients treated with ULTOMIRIS were upper respiratory tract infection, diarrhea, nausea, vomiting, headache, hypertension, and pyrexia. Table 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 STEC-HUS, died due to pretreatment cerebral arterial thrombosis.

Table 11: 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 (%)
*
Graded per CTCAE v5.0.
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.
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)

Clinically relevant adverse reactions include viral tonsilitis (in <10% of patients) and infusion-related reactions (in 3% of patients).

Table 12: 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 (%)
*
Graded per CTCAE v5.0.
Grouped term includes nasopharyngitis, pharyngitis, upper respiratory tract infection, rhinitis, viral upper respiratory tract infection, rhinovirus infection, viral pharyngitis, rhinorrhea, and oropharyngeal pain.
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)

Clinically relevant adverse reactions in <10% of patients include viral infection.

Table 13: 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 (%)
*
Grouped term includes nasopharyngitis, pharyngitis, upper respiratory tract infection, rhinitis, viral upper respiratory tract infection, rhinovirus infection, viral pharyngitis, rhinorrhea, and oropharyngeal pain
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)

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 [see Clinical Studies (14.3)]. In a randomized, double-blind, placebo-controlled trial (ALXN1210-MG-306), the most frequent adverse reactions (≥10%) with ULTOMIRIS were diarrhea and upper respiratory tract infection. Table 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 [see Warnings and Precautions (5.2)]. 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 14: 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)

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