What is the dosing regimen for eculizumab (eculizumab, a C5 inhibitor) in patients with paroxysmal nocturnal hemoglobinuria (PNH) or atypical hemolytic uremic syndrome (aHUS)?

C5 Inhibitor Dosing for PNH and aHUS

Eculizumab Dosing for Paroxysmal Nocturnal Hemoglobinuria (PNH)

For PNH, administer eculizumab 900 mg weekly for 4 weeks, followed by 1200 mg at week 5, then 1200 mg every 2 weeks thereafter. 1, 2

Detailed Dosing Algorithm

• Induction phase: 900 mg IV weekly for the first 4 doses (weeks 1-4) 1
• Transition dose: 1200 mg IV at week 5 1
• Maintenance phase: 1200 mg IV every 14 days indefinitely 1, 2

Pre-Treatment Requirements

• Meningococcal vaccination is mandatory at least 2 weeks before initiating eculizumab, as terminal complement blockade increases risk of invasive meningococcal disease 3, 2, 4
• Administer quadrivalent meningococcal conjugate vaccine (A, C, W, Y) and serogroup B meningococcal vaccine 3
• Provide long-term antimicrobial prophylaxis with penicillin (or macrolides for penicillin-allergic patients) for the duration of treatment 3

Monitoring Parameters

• Hemoglobin and reticulocyte count to assess treatment response 1
• Surveillance for breakthrough hemolysis (dark urine, fatigue, abdominal pain) 1
• LDH, haptoglobin, and indirect bilirubin as markers of hemolysis 1

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Eculizumab Dosing for Atypical Hemolytic Uremic Syndrome (aHUS)

For aHUS, initiate eculizumab 900 mg weekly for 4 weeks, followed by 1200 mg at week 5, then 1200 mg every 2 weeks, with treatment duration of at least 6 months before considering discontinuation. 3, 2

Detailed Dosing Algorithm

• Induction phase: 900 mg IV weekly for 4 doses (weeks 1-4) 2
• Transition dose: 1200 mg IV at week 5 2
• Maintenance phase: 1200 mg IV every 14 days 3, 2
• Minimum treatment duration: At least 6 months, with discontinuation only after minimum 3 months of stabilized/normalized renal function 3

Critical Timing Considerations

Initiating appropriate treatment within 4-8 hours from diagnosis is essential, as delays are associated with increased morbidity and mortality. 3

• If aHUS is suspected, transfer the patient to a rare disease reference center promptly to minimize diagnostic delay 3
• Do not wait for genetic testing results before initiating eculizumab 3

Pre-Treatment Requirements

• Meningococcal vaccination (quadrivalent A, C, W, Y and serogroup B) is required, though response may be hampered by immunosuppression 3
• Long-term antimicrobial prophylaxis with penicillin (or macrolides if penicillin-allergic) for duration of eculizumab treatment 3

Special Populations

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 leads to resistance to anti-C5 monoclonal antibodies. 3

Treatment Duration and Discontinuation

• Administer treatment for at least 6 months before considering discontinuation 3
• Discontinue only after minimum 3 months of stabilized/normalized renal function 3
• Risk of relapse after discontinuation is 10-20%, potentially leading to aHUS recurrence and renal failure 3
• Thoroughly assess risk factors prior to discontinuation decision 3
• Close patient monitoring after discontinuation is mandatory 3
• If recurrence occurs, reinitiate C5 inhibitor treatment 3

Monitoring During Treatment

• Monitor C3, C4, CH50 (classical pathway hemolytic activity), and AP50 (alternate pathway hemolytic activity) if extending the interval of C5 inhibitor administration 3
• Assess hemolytic anemia markers (LDH, haptoglobin, schistocytes), thrombocytopenia, and renal function 3
• Monitor for systemic manifestations and consider patient's genetic and immunologic background 3

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Pregnancy-Related aHUS

Women who develop aHUS triggered by pregnancy benefit from C5 inhibitors, which are instrumental in resolving thrombotic microangiopathy. 3

• Assess on case-by-case basis 3
• Administer treatment for at least 6 months 3
• Discontinue therapy after minimum 3 months of stabilized/normalized renal function 3

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Ravulizumab as Alternative C5 Inhibitor

Ravulizumab has equivalent efficacy and safety to eculizumab but allows extended dosing intervals of every 4-8 weeks based on patient weight, with reduced infusion time. 3, 5

• Dosing interval: every 4-8 weeks depending on patient weight 5
• Reduces travel to infusion centers, medical visits, and job/school absences 5
• Significantly increases patient and family quality of life while reducing costs 5

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Dose Adjustments for Plasmapheresis or Plasma Exchange

Supplemental doses of eculizumab are required when plasmapheresis, plasma exchange, or fresh frozen plasma infusion is performed, as these procedures remove eculizumab from circulation. 2

• Administer supplemental dose per FDA labeling guidelines 2
• Timing and amount depend on type of procedure performed 2

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Common Pitfalls and Caveats

• Never delay eculizumab initiation waiting for genetic testing results in suspected aHUS 3
• Do not discontinue eculizumab prematurely (before 6 months minimum) in aHUS patients 3
• Screen for Chinese/Japanese ancestry before initiating therapy, as genetic polymorphisms may confer resistance 3
• Ensure meningococcal vaccination is completed at least 2 weeks before starting treatment 3, 2
• Maintain antimicrobial prophylaxis throughout entire treatment duration 3
• Monitor closely for breakthrough hemolysis in PNH patients, which may indicate need for dose adjustment or alternative therapy 1