Generic Name

Ultomiris

Mechanism

• C5 inhibition: Binds to the C5 protein with high affinity, preventing cleavage into C5a and C5b, thereby blocking the formation of the membrane attack complex (MAC) and downstream inflammatory signaling.
• Reduction of intravascular hemolysis: In PNH, it prevents complement‑mediated destruction of red blood cells, decreasing hemoglobinuria and transfusion dependence.
• Prevention of thrombotic microangiopathy: In aHUS, it stops endothelial injury and the cascade that leads to platelet activation and microthrombi formation.
• Modulation of auto‑immune activity: In gMG, it limits complement‑mediated damage to neuromuscular junctions.

Pharmacokinetics

• Absorption: Administered IV; bioavailability 100 %.
• Distribution: Volume of distribution ≈ 4 L; extensive tissue penetration, including CNS at low levels.
• Metabolism: Catabolized by proteolytic enzymes (no hepatic metabolism).
• Elimination: Linear clearance; half‑life ≈ 11–12 days (steady‑state).
• Factors affecting PK: Body weight influences distribution; no adjustment needed for age, sex, or mild hepatic/renal impairment.
• Drug interactions: No clinically significant interactions; monitor for concomitant complement inhibitors.

Indications

• Paroxysmal nocturnal hemoglobinuria – reduce intravascular hemolysis, transfusion requirement, and associated morbidity.
• Atypical hemolytic‑uremic syndrome – prevent thrombotic microangiopathy and preserve renal function.
• Generalized myasthenia gravis (≥ 18 yrs, anti‑AChR antibodies positive, or seronegative with inadequate response to standard therapies).

Contraindications

• Contraindications
• Known hypersensitivity to eculizumab, murine protein, or any excipient.
• Active systemic infection with *Neisseria meningitidis* or other encapsulated bacteria.
• Warnings
• Meningococcal infection: Requires vaccination 2 weeks before first dose (or earlier if emergency).
• Infection risk: Opportunistic infections (e.g., C. difficile, Candida spp.) may occur.
• Pregnancy: Category B; limited data—use only if benefits outweigh risks.

Dosing

• Pneumonia
• *PNH*: 600 mg IV weekly × 4 weeks (loading phase), then 600 mg every 2 weeks.
• *aHUS*: 600 mg IV weekly × 4 weeks, then 900 mg every 2 weeks, with dose escalation to 1200 mg if needed.
• *gMG*: 600 mg IV weekly × 4 weeks, then 600 mg every 2 weeks.
• Administration
• Infusion over 60 min (4th dose 30 min).
• Premedicate with antihistamine/acetaminophen to mitigate infusion reactions.
• Duration
• Chronic therapy required; tapering is generally not recommended due to risk of relapse.

Adverse Effects

• Common
• Headache, back pain, fatigue, infusion reaction (fever, chills).
• Myalgia, arthralgia, diarrhea.
• Serious
• Meningococcal meningitis or sepsis.
• Hepatitis B reactivation (screen & monitor).
• Gastrointestinal perforation (rare).
• Embolism or thrombosis (particularly in aHUS).

Monitoring

• Baseline
• CBC, LDH, haptoglobin, creatinine, coagulation profile.
• Meningococcal vaccine status, HBV serology.
• During therapy
• Hemoglobin & LDH (monthly for first 3 months, then q3‑q6 months).
• Renal function (gMG & aHUS).
• Liver enzymes (HBV reactivation).
• Signs of infection or meningitis.
• Immunogenicity
• Anti‑eculizumab antibodies rare but may necessitate therapy change.

Clinical Pearls

• Vaccine timing is critical: Administer meningococcal conjugate vaccine ≥ 14 days before infusion; if urgent, give empiric prophylaxis (penicillin V or ceftriaxone) and rescue with eculizumab.
• Dose escalation in aHUS: Escalate to ≥ 900 mg q2 wk only after confirming adequate complement blockade and renal stability.
• Infusion reactions: Most are mild; premedication and slowing infusion rate at first dose reduce incidence.
• Renal considerations: Even with normal eGFR, monitor for hemolysis‑related renal injury; adjust therapy promptly.
• Pregnancy & lactation: Limited data – counsel patients on risks; consider alternative therapies if pregnancy is planned.
• Cost & access: Reimbursement eligibility may hinge on confirmed diagnosis and prior therapy failure; early coordination with pharmacy benefit managers is essential.

*For further reading: FDA label (2023), 2022 AHA/ACC guidelines on PNH and aHUS, and the 2023 Revue Médicale des Maladies Auto-immunes.*