Ultomiris - Drug Monograph

Introduction

Ultomiris (ravulizumab-cwvz) is a long-acting complement C5 inhibitor developed by Alexion Pharmaceuticals for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and other complement-mediated disorders. As a successor to eculizumab (Soliris), Ultomiris offers extended dosing intervals while maintaining similar efficacy through its targeted mechanism of action.

Mechanism of Action

Ultomiris is a monoclonal antibody that specifically binds to the complement protein C5 with high affinity, inhibiting its cleavage into C5a and C5b. This prevents the formation of the terminal complement complex (C5b-9), which is responsible for complement-mediated intravascular hemolysis in PNH. By blocking terminal complement activation, Ultomiris reduces hemolysis and thrombotic risk while preserving the proximal complement pathway important for immune defense.

Indications

• Treatment of paroxysmal nocturnal hemoglobinuria (PNH) in adults and children ≥1 month
• Treatment of atypical hemolytic uremic syndrome (aHUS) in adults and children ≥1 month
• Treatment of generalized myasthenia gravis (gMG) in adults who are anti-acetylcholine receptor antibody-positive
• Treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults who are anti-aquaporin-4 antibody-positive

Dosage and Administration

• ≥40 kg: 2,400 mg IV
• 20 to <40 kg: 2,400 mg IV
• 10 to <20 kg: 1,800 mg IV
• 5 to <10 kg: 1,200 mg IV
• ≥1 month to <5 kg: 600 mg IV

• ≥40 kg: 3,000 mg IV
• 20 to <40 kg: 3,000 mg IV
• 10 to <20 kg: 2,400 mg IV
• 5 to <10 kg: 1,800 mg IV
• ≥1 month to <5 kg: 600 mg IV

Administer as intravenous infusion over approximately 4-8 hours (depending on dose). Must be diluted prior to administration. Patients must be vaccinated against Neisseria meningitidis at least 2 weeks prior to first dose.

Pharmacokinetics

Contraindications

• Patients with unresolved Neisseria meningitidis infection
• Patients not currently vaccinated against Neisseria meningitidis (unless risks outweigh benefits)
• Hypersensitivity to ravulizumab or any component of the formulation

Warnings and Precautions

• Meningococcal infection may rapidly become life-threatening or fatal if not recognized and treated early
• Monitor patients for early signs of meningococcal infections
• Vaccinate patients at least 2 weeks prior to administration

• Other serious infections, particularly encapsulated bacteria
• Infusion-related reactions
• Thrombotic microangiopathy (TMA) complications after discontinuation
• Monitoring for hemolysis after discontinuation

Drug Interactions

No formal drug interaction studies conducted. However:

• May interfere with response to vaccinations (live vaccines not recommended)
• Theoretical potential for interactions with other complement inhibitors
• No expected interactions with cytochrome P450 substrates

Adverse Effects

• Upper respiratory tract infection
• Headache
• Diarrhea
• Nausea
• Back pain
• Arthralgia
• Fatigue
• Pyrexia

• Meningococcal infections
• Other serious infections
• Infusion reactions
• Thrombotic events

Monitoring Parameters

• Signs/symptoms of meningococcal infection (fever, headache, stiff neck, photophobia)
• Complete blood count with reticulocytes
• Lactate dehydrogenase (LDH) levels
• Haptoglobin levels
• Renal function (for aHUS patients)
• Neurological status (for gMG and NMOSD patients)
• Infusion reactions during administration
• Vaccination status prior to initiation

Patient Education

• Immediately report any signs of meningococcal infection (fever, severe headache with nausea/vomiting, stiff neck, sensitivity to light)
• Carry patient safety card at all times
• Understand importance of meningococcal vaccination
• Report any signs of infection promptly
• Do not miss scheduled doses
• Inform all healthcare providers about Ultomiris therapy
• Be aware of potential risks during pregnancy (report pregnancy to provider)
• Understand need for monitoring and regular follow-up

References

1. Ultomiris [package insert]. Boston, MA: Alexion Pharmaceuticals, Inc.; 2023. 2. Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, et al. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: phase 3 study. Blood. 2019;133(6):530-539. 3. Legendre CM, Licht C, Muus P, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368(23):2169-2181. 4. Pittock SJ, Berthele A, Fujihara K, et al. Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder. N Engl J Med. 2019;381(7):614-625. 5. Howard JF Jr, Utsugisawa K, Benatar M, et al. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol. 2017;16(12):976-986.