ULTOMIRIS® (ravuizumab-cwvz) injection for intravenous use 300 mg/30 mL vial
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WHAT IS PNH?

PNH (paroxysmal nocturnal hemoglobinuria) is a chronic, catastrophic disease characterized by complement-mediated intravascular hemolysis4-6

PNH is a hemolytic disease that originates
in the hematopoietic stem cell5-7

Normal blood cell

GPI-anchored proteins

In healthy RBCs, GPI-anchored proteins (CD55 and CD59)a defend against complement-mediated hemolysis.

PNH blood cell

No GPI-anchored proteins

In PNH, an acquired PIG-A mutation can lead to the complete or partial absence of GPI-anchored proteins.

aComplement-regulatory proteins CD55 (decay-accelerating factor) and CD59 (membrane inhibitor of reactive lysis) defend against the complement pathway by regulating the formation and stability of the C3 convertase and blocking the assembly of the membrane attack complex, respectively.8

GPI=glycosylphosphatidylinositol; PIG-A=phosphatidylinositol glycan anchor biosynthesis class A; RBC=red blood cell.

The continuously active system attacks defective RBCs, causing intravascular hemolysis, the underlying cause of progressive morbidities, which results in potentially life-threatening complications of intravascular hemolysis.9-15

The role of complement

Complement attack leads to devastating systemic consequences in PNH14-16

Complement is a complex array of more than 20 proteins present in the blood and plays a fundamental role in the body’s innate immune response against infection. Insufficient regulation of the complement cascade can have highly destructive effects17

In PNH, the deficiency of complement inhibitors leads to chronic, uncontrolled complement activation, resulting in chronic hemolysis and granulocyte and platelet activation17,18

Consequences of chronic, uncontrolled complement activation14-16

Tap to enlarge

Graphic is a simplified representation of the complement cascade.

MAC=membrane attack complex

  • Terminal complement activation begins with cleavage of C5, resulting in the formation of the MAC, and intravascular hemolysis18

Control of C5 levels plays an important role in effectively managing PNH4,5,19

Complement attack leads to complications in PNH15,20

Tap to enlarge

Signs and symptoms of PNH include

Tap to enlarge

aMale patients only (n=410).11

How ULTOMIRIS works

ULTOMIRIS is built on the foundation of eculizumab, resulting in a molecule with a ~4x longer half-life.1,25,26,a

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ULTOMIRIS efficacy

In clinical studies, ULTOMIRIS demonstrated sustained complement inhibition for 8 weeks. See the primary endpoints.1-3

SEE THE DATA

aThe mean (SD) terminal elimination half-life and clearance of ravulizumab-cwvz in patients with PNH are 49.7 (8.9) days and 0.08 (0.022) L/day, respectively. Half-life of eculizumab is 11.25-17.25 days.

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.