What are the clinical indications for Ravulizumab (ravulizumab)?

Clinical Indications for Ravulizumab

Ravulizumab is FDA-approved for four specific indications: paroxysmal nocturnal hemoglobinuria (PNH) in adults, atypical hemolytic uremic syndrome (aHUS) in adults and pediatric patients, generalized myasthenia gravis (gMG) in adults, and neuromyelitis optica spectrum disorder (NMOSD) in adults. 1

FDA-Approved Indications

1. Paroxysmal Nocturnal Hemoglobinuria (PNH)

• Adult patients with PNH who require complement C5 inhibition to control intravascular hemolysis 1, 2
• Ravulizumab demonstrated non-inferiority to eculizumab in complement inhibitor-naïve patients, with 43.5% achieving LDH normalization and 76.6% avoiding transfusions over 52 weeks 3
• Long-term data (up to 6 years) shows durable control of terminal complement activity with a low incidence of major adverse vascular events (0.7-1.4 per 100 patient-years) and five-fold reduction in mortality risk compared to untreated patients 4

2. Atypical Hemolytic Uremic Syndrome (aHUS)

• Adult and pediatric patients with aHUS to inhibit complement-mediated thrombotic microangiopathy 1, 5
• In treatment-naïve patients, ravulizumab resolved thrombotic microangiopathy in 54% of adults and 78% of pediatric patients within 26 weeks 5
• Effective in pregnancy-triggered aHUS, where C5 inhibitors are instrumental in resolving TMA 6
• Critical timing consideration: Treatment should be initiated within hours of diagnosis to minimize morbidity and mortality 7

3. Generalized Myasthenia Gravis (gMG)

• Adult patients with gMG who are anti-acetylcholine receptor (AChR) antibody-positive 1
• Pharmacokinetic data demonstrates adequate drug exposure with maintenance dosing achieving mean trough levels of 587 mcg/mL 1

4. Neuromyelitis Optica Spectrum Disorder (NMOSD)

• Adult patients with NMOSD who are anti-aquaporin-4 (AQP4) antibody-positive 1
• Pharmacokinetic parameters show sustained drug levels with mean trough concentrations of 796.9 mcg/mL at steady state 1

Dosing Advantages Over Eculizumab

Ravulizumab offers extended dosing intervals of every 4-8 weeks (based on patient weight) compared to eculizumab's every 2-3 weeks schedule, significantly reducing infusion center visits and improving quality of life 8, 5

• Pediatric patients <20 kg: every 4 weeks
• Pediatric patients ≥20 kg and adults: every 8 weeks 1

Mandatory Pre-Treatment Requirements

Meningococcal Vaccination (Critical Safety Measure)

• All patients must receive quadrivalent meningococcal conjugate vaccine (serogroups A, C, W, Y) and meningococcal B vaccine at least 2 weeks before initiating ravulizumab 6, 7
• Long-term antimicrobial prophylaxis with penicillin is required due to increased risk of invasive meningococcal disease from terminal complement blockade 6, 7

Additional Pre-Treatment Screening

• Hepatitis B and C antibody testing 9
• Baseline immunoglobulin levels (IgG, IgM, IgA) 9

Important Clinical Caveats

Genetic Resistance

• Patients of Chinese and/or Japanese descent may not respond to C5 inhibitors due to polymorphic variants of the C5 gene (c.2654 G→A, c.2653 C→T) in heterozygous state, which confers resistance to anti-C5 monoclonal antibodies 6

Treatment Discontinuation Risk

• Discontinuing ravulizumab carries 10-20% risk of aHUS recurrence and potential renal failure 6
• Patients must be thoroughly assessed for risk factors before considering discontinuation, and close monitoring is mandatory if treatment is stopped 6
• If recurrence occurs, immediate reinitiation of C5 inhibitor is recommended 6

Supplemental Dosing Requirements

• Concomitant plasmapheresis (PE), plasma exchange (PP), or intravenous immunoglobulin (IVIg) treatment requires supplemental dosing of ravulizumab due to removal or interference with the monoclonal antibody 1

Drug Interaction Warning

• Neonatal Fc receptor (FcRn) blocker treatment may decrease serum ravulizumab concentrations by interfering with the endosomal FcRn recycling mechanism 1

Monitoring During Treatment

• Serum free C5 levels should be maintained <0.5 mcg/mL for optimal complement inhibition 3, 4
• Monitoring of C3, C4, CH50, and AP50 is useful if extending the dosing interval 6
• Breakthrough hemolysis events are rare when free C5 remains adequately suppressed, with only 1.8% of events associated with suboptimal C5 inhibition 4