Ravulizumab

Ravulizumab is a long-acting humanised monoclonal antibody against complement protein C5, engineered from eculizumab to prolong half-life, given intravenously every 8 weeks (every 4 weeks in some paediatric bands), used in paroxysmal nocturnal haemoglobinuria, atypical haemolytic uraemic syndrome, generalised myasthenia gravis with antibodies to acetylcholine receptor, and neuromyelitis optica spectrum disorder with antibodies to aquaporin 4. It carries the same meningococcal infection risk as eculizumab.

Class. Complement C5 inhibitor monoclonal antibody, long-acting.

Mechanism. Binds C5 and blocks its cleavage, preventing membrane attack complex formation, with pH-dependent dissociation that recycles the antibody through the neonatal Fc receptor and extends its life.

Pharmacokinetics. Intravenous half-life about 50 days, steady state after the loading dose, with free C5 suppressed over 99 percent between doses.

Paroxysmal nocturnal haemoglobinuria, atypical haemolytic uraemic syndrome, generalised myasthenia gravis and neuromyelitis optica spectrum disorder (adults, by body weight).

• 40 to under 60 kg: loading 2400 mg, then 3000 mg every 8 weeks starting 2 weeks later.

• 60 to under 100 kg: loading 2700 mg, then 3300 mg every 8 weeks starting 2 weeks later.

• 100 kg and over: loading 3000 mg, then 3600 mg every 8 weeks starting 2 weeks later.

• Maximum dose: 3600 mg for each infusion.

Paediatric paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome (by weight).

• 5 to under 10 kg: loading 600 mg, maintenance 300 mg every 4 weeks.

• 10 to under 20 kg: loading 600 mg, maintenance 600 mg every 4 weeks.

• 20 to under 30 kg: loading 900 mg, maintenance 2100 mg every 8 weeks.

• 30 to under 40 kg: loading 1200 mg, maintenance 2700 mg every 8 weeks.

• 40 kg and over: adult regimen.

Supplemental doses. After plasma exchange or plasma infusion, give a supplemental dose within 4 hours of the end of the procedure, using the weight-based table on the product label.

Switching from eculizumab. Give the ravulizumab loading dose 2 weeks after the last eculizumab dose.

Mandatory preparation. Required for every patient on a complement C5 inhibitor: meningococcal vaccines (conjugate ACWY and serogroup B) at least 2 weeks before the first dose, and antibiotic prophylaxis (for example penicillin V 500 mg twice daily) during treatment and for 8 months after the last dose.

Contraindications. Unresolved serious Neisseria meningitidis infection, and patients not currently vaccinated unless prophylaxis is given in an urgent situation. Hypersensitivity.

Boxed-warning-level risks. Life-threatening and fatal meningococcal infections and other encapsulated bacterial infections.

Adverse effects. Common: headache, upper respiratory infection, diarrhoea, nausea, pyrexia, fatigue, back pain, infusion reactions. Serious: meningococcal disease, other encapsulated bacterial infection, thrombotic microangiopathy or haemolysis on stopping, hypersensitivity, immunogenicity.

Major interactions. Plasma exchange and plasma infusion (reduce levels; supplemental doses), live vaccines (avoid), and other immunosuppressants add infection risk.

Common prescribing errors. Starting without meningococcal vaccination or prophylaxis; omitting supplemental doses after plasma exchange; applying the eculizumab 2 week interval; stopping prophylaxis too early because of the long half-life.

Special groups.

• Pregnancy: limited data; continue where the benefit outweighs risk.

• Breastfeeding: limited data; likely low transfer into milk.

• Children: weight-based as stated.

• Older adults: no adjustment.

• Kidney impairment: no adjustment.

• Liver impairment: no adjustment expected.

• Region: meningococcal vaccine availability and cost limit use in East Africa; confirm vaccine supply and adherence to prophylaxis before starting, and issue a patient alert card.

Formulations. 300 mg/3 mL and 1100 mg/11 mL vials; dilute in 0.9 percent sodium chloride to a final concentration of 5 mg/mL and infuse over about 45 to 110 minutes depending on dose (rate limited by weight band). Observe for at least 1 hour after the infusion. Store at 2 to 8 degrees Celsius.

Baseline. Meningococcal and pneumococcal vaccination status, full blood count, lactate dehydrogenase, haptoglobin, creatinine, urinalysis, hepatitis B and C and HIV serology, and infection risk review.

Monitoring. Haemolysis markers (lactate dehydrogenase, haemoglobin) in paroxysmal nocturnal haemoglobinuria; creatinine, platelets and lactate dehydrogenase in atypical haemolytic uraemic syndrome; infection symptoms at each visit; adherence to prophylaxis.

After stopping. Monitor for at least 8 weeks (paroxysmal nocturnal haemoglobinuria) or at least 12 weeks (atypical haemolytic uraemic syndrome) for haemolysis or thrombotic microangiopathy.

Stop or hold thresholds. Active meningococcal infection or other serious encapsulated infection (treat urgently), anaphylaxis, or no clinical benefit.

Referral and escalation. Specialist initiated. Fever in any patient on treatment is an emergency: urgent assessment and empirical intravenous antibiotics such as ceftriaxone 2 g every 12 hours for suspected meningococcal disease, without waiting for results.