ULTOMIRIS® (ravuizumab-cwvz) injection for intravenous use 300 mg/30 mL vial
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ULTOMIRIS was studied in the largest phase 3 PNH program encompassing a clinically diverse patient population, including complement inhibitor–naïve and eculizumab-treated patients.1-3

ULTOMIRIS provided immediate, complete, and sustained C5 inhibition in clinical studies. C5 inhibition was observed by the end of the first infusion.1-3,33

Mean free C5 levels over time in patients treated with ULTOMIRIS and eculizumab

  • ULTOMIRIS met its co-primary endpoints of non-inferiority in transfusion avoidance and LDH normalization

Patients treated with ULTOMIRIS experienced fewer instances of breakthrough hemolysis vs. those treated with eculizumab

  • Breakthrough hemolysis was defined as at least 1 new or worsening symptom or sign of intravascular hemolysis in the presence of elevated LDH ≥2 x ULN, after prior LDH reduction to <1.5 x ULN on therapy
  • In the complement inhibitor–naïve study, 4.0% of patients treated with ULTOMIRIS experienced breakthrough hemolysis vs. 10.7% with eculizumab
  • In the ULTOMIRIS switch study, no patients treated with ULTOMIRIS experienced breakthrough hemolysis vs. 5.1% of patients treated with eculizumab

LDH=lactate dehydrogenase; ULN=upper limit of normal.

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Free C5 levels below 0.5 μg/mL were correlated with maximal intravascular hemolysis control and complete terminal complement inhibition in clinical studies

aThe horizontal line in the middle of each box indicates the median, a square indicates the mean for ULTOMIRIS, and a circle indicates the mean for eculizumab. The top and bottom borders of the box mark the 75th and 25th percentiles, respectively. The whiskers represent the 1.5 interquartile range (IQR) of the lower quartile and upper quartile. Outliers are represented by asterisks beyond the whiskers. Dashed horizontal lines indicate serum-free C5 concentration of 0.5 μg/mL.

bThe complement inhibitor–naïve study [ALXN1210-PNH-301; NCT02946463] was a 26-week, multicenter, open-label, randomized, active-controlled, noninferiority, phase 3 study conducted in 246 patients naïve to complement inhibitor treatment prior to study entry.

A Gyros-based fluorescence assay was used for patients who received ULTOMIRIS, and an electrochemiluminescence immunoassay was used for patients who received eculizumab. Baseline was defined as the last nonmissing value before the first dose of study drug.

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Free C5 levels below 0.5 μg/mL were correlated with maximal intravascular hemolysis control and complete terminal complement inhibition in clinical studies

aThe horizontal line in the middle of each box indicates the median, a square indicates the mean for ULTOMIRIS, and a circle indicates the mean for eculizumab. The top and bottom borders of the box mark the 75th and 25th percentiles, respectively. The whiskers represent the 1.5 interquartile range (IQR) of the lower quartile and upper quartile. Outliers are represented by asterisks beyond the whiskers. Dashed horizontal lines indicate serum-free C5 concentration of 0.5 μg/mL.

cThe ULTOMIRIS switch study [ALXN1210-PNH-302; NCT03056040] was a 26-week, multicenter, open-label, randomized, active-controlled, noninferiority, phase 3 study conducted in 195 patients with PNH who were clinically stable after having been treated with eculizumab for at least the past 6 months.

A Gyros-based fluorescence assay was used for patients who received ULTOMIRIS, and an electrochemiluminescence immunoassay was used for patients who received eculizumab. Baseline was defined as the last nonmissing value before the first dose of study drug.

ULTOMIRIS was evaluated in two phase 3, open-label, randomized, active-controlled, multicenter, noninferiority studies1-3

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The efficacy and safety of ULTOMIRIS were assessed in adult (≥18 years of age) patients with PNH who were treated with and clinically stable on eculizumab for ≥6 monthsa,b

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Across both studies, the clinically diverse patient population included males and females aged ≥18 years in up to 25 countries, with red and white blood cell clone sizes of ≥5% with and without aplastic anemia

Complement Inhibitor-Naïve Study Endpoints

Co-Primary
  • Transfusion avoidanceg
  • LDH normalization
Secondary
  • Percent change from baseline in LDH levels
  • Change in fatigue (FACIT-Fatigue)
  • Proportion of patients with breakthrough hemolysish
  • Proportion of patients with stabilized hemoglobin

aPopulation included male and female patients ≥18 years or older in 25 countries.

bIn the complement inhibitor–naïve study, 98% of patients had a documented PNH-associated condition diagnosed prior to enrollment in the trial: anemia (85%), hemoglobinuria (63%), history of aplastic anemia (32%), history of renal failure (12%), myelodysplastic syndrome (5%), pregnancy (3%), and other (16%).

cLoading dose for patients weighing ≥40 to <60 kg=2400 mg; loading dose for patients weighing ≥60 to <100 kg=2700 mg; loading dose for patients weighing ≥100 kg=3000 mg.

dMaintenance dose for patients weighing ≥40 to <60 kg=3000 mg; maintenance dose for patients weighing ≥60 to <100 kg=3300 mg; maintenance dose for patients weighing ≥100 kg=3600 mg.

eEculizumab induction dose=600 mg.

fEculizumab maintenance dose=900 mg.

gTransfusion avoidance was considered as achieved only by the patients who did not receive a transfusion and did not meet the protocol-specified guidelines for transfusion from baseline to Day 183.

hBreakthrough hemolysis was defined as at least 1 new or worsening symptom or sign of intravascular hemolysis in the presence of elevated LDH ≥2x ULN, after prior LDH reduction to <1.5x ULN on therapy.

FACIT=Functional Assessment of Chronic Illness Therapy.

The efficacy and safety of ULTOMIRIS were assessed in adult (≥18 years of age) patients with PNH who were treated with and clinically stable on eculizumab for ≥6 monthsa,b

Tap to enlarge

Across both studies, the clinically diverse patient population included males and females aged ≥18 years in up to 25 countries, with red and white blood cell clone sizes of ≥5% with and without aplastic anemia

ULTOMIRIS Switch Study Endpoints

Primary
  • LDH percent change from baseline
Secondary
  • Proportion of patients with breakthrough hemolysisf
  • Change in fatigue (FACIT-Fatigue)
  • Transfusion avoidanceg
  • Proportion of patients with stabilized hemoglobin

aPopulation included male and female patients ≥18 years of age in 11 countries.

bIn the ULTOMIRIS switch study, 95% of patients had a 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%).

cLoading dose for patients weighing ≥40 to <60 kg=2400 mg; loading dose for patients weighing ≥60 to <100 kg=2700 mg; loading dose for patients weighing ≥100 kg=3000 mg.

dMaintenance dose for patients weighing ≥40 to <60 kg=3000 mg; maintenance dose for patients weighing ≥60 to <100 kg=3300 mg; maintenance dose for patients weighing ≥100 kg=3600 mg.

eEculizumab maintenance dose=900 mg.

fBreakthrough hemolysis was defined as at least 1 new or worsening symptom or sign of intravascular hemolysis in the presence of elevated LDH >2x ULN, after prior LDH reduction to <1.5x ULN on therapy.

gTransfusion avoidance was considered as achieved only by the patients who did not receive a transfusion and did not meet the protocol-specified guidelines for transfusion from baseline to Day 183.

ULTOMIRIS demonstrated robust and sustained efficacy across all endpoints vs. eculizumab, in noninferiority studies, while allowing patients every-8-week dosing1-3

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ULTOMIRIS demonstrated robust and sustained efficacy across a clinically diverse patient population

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aFor the transfusion avoidance endpoint, treatment differences (95% CIs) are based on estimated differences in percent with 95% CI.

bFor the lactate dehydrogenase normalization endpoint, the adjusted prevalence within each treatment is displayed.

cThere was no observable difference in fatigue between ULTOMIRIS and eculizumab after 26 weeks of treatment compared with baseline, as measured by the FACIT-Fatigue instrument.

Patient-reported fatigue may be an under- or overestimation, because patients were not blinded to treatment assignment.

Patients treated with eculizumab were effectively switched to ULTOMIRIS

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aThere was no observable difference in fatigue between ULTOMIRIS and eculizumab after 26 weeks of treatment compared with baseline, as measured by the FACIT-Fatigue instrument. Patient-reported fatigue may be an under- or overestimation, because patients were not blinded to treatment assignment.

bFor the transfusion avoidance endpoint, treatment differences (95% CIs) are based on estimated differences in percent with 95% CI.

The ULTOMIRIS safety profile was similar to that of eculizumab as observed in the largest phase 3 PNH clinical program1

Adverse events reported in 5% or more of ULTOMIRIS-treated patients in complement inhibitor-naïve and eculizumab-experienced studies

Number (%) of Patients

System Organ Class Preferred Term
Eculizumab
n=219
ULTOMIRIS
n=222

Gastrointestinal disorders

Diarrhea
12 (5)
19 (9)
Nausea
19 (9)
19 (9)
Abdominal pain
16 (7)
13 (6)

General disorders and administration site conditions

Pyrexia
18 (8)
15 (7)

Infections and infestations

Upper respiratory tract infectiona
86 (39)
86 (39)

Musculoskeletal and connective tissue disorders

Pain in extremity
11 (5)
14 (6)
Arthralgia
12 (5)
11 (5)

Nervous system disorders

Headache
57 (26)
71 (32)
Dizziness
14 (6)
12 (5)

ULTOMIRIS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the ULTOMIRIS REMS, prescribers must be certified in the program. Enrollment in the ULTOMIRIS REMS program and additional information are available by telephone: 1-888-765-4747 or at www.ultomirisrems.com

  • The most frequent adverse drug reactions (>10%) with ULTOMIRIS were upper respiratory tract infection and headache
  • Serious adverse reactions were reported in 15 (6.8%) patients 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

aIncludes the preferred terms nasopharyngitis, upper respiratory tract infection, oropharyngeal pain, viral upper respiratory tract infection, rhinitis, respiratory tract infection, rhinorrhea, pharyngitis, and upper respiratory tract inflammation.

Dosing

ULTOMIRIS has weight-based dosing with 6-7 infusions per year1,a for adult patients with PNH.

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aStarting 2 weeks after the initial loading dose, maintenance doses are administered once every 8 weeks.

INDICATION & IMPORTANT SAFETY INFORMATION for ULTOMIRIS® (ravulizumab-cwvz), INCLUDING BOXED WARNING

INDICATION

Paroxysmal Nocturnal Hemoglobinuria (PNH)

ULTOMIRIS is indicated for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH).

IMPORTANT SAFETY INFORMATION

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.

  • 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 2 weeks prior to administering the first dose of ULTOMIRIS, unless the risks of delaying ULTOMIRIS therapy outweigh the risk of developing a meningococcal infection. See Warnings and Precautions 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 a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the ULTOMIRIS REMS, prescribers must enroll in the program. Enrollment in the ULTOMIRIS REMS program and additional information are available by telephone: 1-888-765-4747 or at www.ultomirisrems.com.

CONTRAINDICATIONS

ULTOMIRIS is contraindicated in:

  • Patients with unresolved Neisseria meningitidis infection.
  • Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying ULTOMIRIS treatment outweigh the risks of developing a meningococcal infection.

WARNINGS AND PRECAUTIONS
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 patients with PNH 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, 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.

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.

Other Infections

ULTOMIRIS blocks terminal complement activation; therefore patients may have increased susceptibility to encapsulated bacteria infections, especially infections caused by Neisseria meningitis but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae. If ULTOMIRIS therapy is administered to patients with active systemic infections, monitor closely for signs and symptoms of worsening infection.

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 re-appearance 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.

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.

Infusion Reactions

Administration of ULTOMIRIS may result in infusion reactions. In clinical trials, 5 out of 296 patients treated with ULTOMIRIS experienced infusion reactions (lower back pain, drop in blood pressure, infusion-related pain, elevation in blood pressure and limbs 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.

ADVERSE REACTIONS

Adverse reactions reported in 5% or more of patients treated with ULTOMIRIS vs. Eculizumab was Upper respiratory tract infection (39% vs 39%), Headache (32% vs. 26%), Diarrhea (9% vs. 5%), Nausea (9% vs. 9%), Pyrexia (7% vs 8%), Pain in extremity (6% vs. 5%), Abdominal pain (6% vs. 7%), Dizziness (5% vs. 6%), Arthralgia (5% vs. 5%).

Serious adverse reactions were reported in 15 (6.8%) patients 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.

Please see accompanying full Prescribing Information for ULTOMIRIS, including Boxed WARNING regarding serious and life-threatening meningococcal infections/sepsis.