Introduction
Ravulizumab (Ultomiris®) is a long-acting C5 complement inhibitor monoclonal antibody approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). It represents a significant advancement in complement-mediated disease management with an extended dosing interval compared to its predecessor, eculizumab.
Mechanism of Action
Ravulizumab is a humanized monoclonal antibody that binds specifically to the C5 complement protein with high affinity. By binding to C5, ravulizumab inhibits its cleavage into C5a (anaphylatoxin) and C5b, thereby preventing the formation of the terminal complement complex (C5b-9). This inhibition blocks complement-mediated intravascular hemolysis in PNH and complement-mediated thrombotic microangiopathy in aHUS.
Indications
- Paroxysmal nocturnal hemoglobinuria (PNH): Treatment of adult and pediatric patients (≥1 month old)
- Atypical hemolytic uremic syndrome (aHUS): Treatment of adult and pediatric patients (≥1 month old) to inhibit complement-mediated thrombotic microangiopathy
Dosage and Administration
PNH and aHUS dosing (adults and pediatric patients ≥20 kg):- Loading dose: 2,400-3,000 mg based on weight
- Maintenance dose: 3,000-3,600 mg every 8 weeks based on weight
- Loading dose: 600 mg
- Maintenance dose: 300 mg every 4 weeks
- Loading dose: 900 mg
- Maintenance dose: 1,200 mg every 4 weeks
- Intravenous infusion over approximately 4-8 hours
- Must be diluted in 0.9% Sodium Chloride Injection, USP
- Requires meningococcal vaccination at least 2 weeks prior to first dose
Pharmacokinetics
- Absorption: Administered intravenously, achieving 100% bioavailability
- Distribution: Volume of distribution approximately 5.0-6.5 L
- Metabolism: Degraded via proteolytic enzymes throughout the body
- Elimination: Terminal half-life approximately 49.7 days
- Clearance: Linear clearance of approximately 0.08 L/day
Contraindications
- Patients with unresolved serious Neisseria meningitidis infection
- Patients who are not currently vaccinated against Neisseria meningitidis unless the risks of delaying treatment outweigh the risks of developing meningococcal infection
Warnings and Precautions
Boxed Warning: Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors. Meningococcal vaccination must be administered at least 2 weeks prior to initiating therapy. Additional warnings:- Monitor for early signs of meningococcal infection
- Other serious infections, particularly those caused by encapsulated bacteria
- Infusion-related reactions
- Thrombosis prevention and management in PNH patients after discontinuation
Drug Interactions
- No formal drug interaction studies conducted
- Theoretical potential for interactions with other complement inhibitors
- Caution with other immunosuppressive agents due to increased infection risk
Adverse Effects
Most common adverse reactions (≥10%):- Upper respiratory tract infection
- Headache
- Diarrhea
- Nausea
- Back pain
- Arthralgia
- Fatigue
- Meningococcal infections
- Other serious infections
- Infusion reactions
- Hepatitis B reactivation
Monitoring Parameters
- Complete blood count with reticulocytes
- Lactate dehydrogenase (LDH) levels
- Haptoglobin levels
- Renal function (creatinine, BUN)
- Signs and symptoms of infection
- Infusion reactions during administration
- Hepatitis B screening prior to initiation
Patient Education
- Understand the increased risk of serious meningococcal infections
- Recognize early signs of infection (fever, headache, stiff neck, confusion)
- Carry patient safety card at all times
- Complete required vaccinations before starting treatment
- Report any signs of infusion reactions during treatment
- Understand importance of compliance with dosing schedule
- Inform all healthcare providers about ravulizumab therapy
References
1. US Food and Drug Administration. Ultomiris (ravulizumab) prescribing information. 2022. 2. Kulasekararaj AG, Hill A, Rottinghaus ST, et al. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor–experienced adult patients with PNH: the 302 study. Blood. 2019;133(6):540-549. 3. 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: the 301 study. Blood. 2019;133(6):530-539. 4. 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. 5. Greenbaum LA, Fila M, Ardissino G, et al. Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome. Kidney Int. 2016;89(3):701-711.