Tocilizumab

Tocilizumab is a humanised monoclonal antibody against the interleukin 6 receptor, given intravenously or subcutaneously, used in rheumatoid arthritis, giant cell arteritis, systemic and polyarticular juvenile idiopathic arthritis, cytokine release syndrome and, in selected severe cases, COVID-19 pneumonia. It suppresses fever and C-reactive protein, which can mask infection.

Class. Interleukin 6 receptor antagonist monoclonal antibody.

Mechanism. Binds soluble and membrane-bound interleukin 6 receptors, blocking interleukin 6 signalling and downstream acute phase response, B cell differentiation and T cell activation.

Pharmacokinetics. Nonlinear, target-mediated clearance. Half-life is 11 to 13 days at 4 mg/kg and up to 21 days at 8 mg/kg intravenously; about 5 to 13 days subcutaneously.

Rheumatoid arthritis (intravenous). 4 mg/kg every 4 weeks, increased to 8 mg/kg every 4 weeks as response requires. Maximum dose: 800 mg for each infusion.

Rheumatoid arthritis (subcutaneous). 162 mg every other week for patients under 100 kg, increased to weekly if response is inadequate; 162 mg weekly for patients of 100 kg or more.

Giant cell arteritis. 162 mg subcutaneously once weekly with a glucocorticoid taper over 26 weeks; every other week dosing is used in some patients in remission.

Systemic juvenile idiopathic arthritis (2 years and over). 12 mg/kg intravenously every 2 weeks for under 30 kg; 8 mg/kg every 2 weeks for 30 kg and over.

Polyarticular juvenile idiopathic arthritis (2 years and over). 10 mg/kg intravenously every 4 weeks for under 30 kg; 8 mg/kg every 4 weeks for 30 kg and over.

Cytokine release syndrome (specialist). 8 mg/kg intravenously (12 mg/kg if under 30 kg) as a single dose over 60 minutes; up to 3 further doses at least 8 hours apart; maximum 800 mg for each dose.

Severe COVID-19 pneumonia (specialist, limited use). 8 mg/kg intravenously as a single dose, maximum 800 mg, with a corticosteroid, in patients with hypoxia and raised inflammatory markers.

Loading dose. None.

Contraindications. Active serious infection including tuberculosis, and hypersensitivity. Avoid in active diverticulitis or with a history of bowel perforation risk.

Boxed-warning-level risks. Serious infections leading to hospitalisation or death, including tuberculosis, invasive fungal, bacterial, viral and opportunistic infections.

Adverse effects. Common: upper respiratory infection, headache, hypertension, raised ALT, hypercholesterolaemia, injection site reactions. Serious: neutropenia, thrombocytopenia, gastrointestinal perforation (especially with diverticular disease and glucocorticoids), hepatotoxicity including liver injury, anaphylaxis, demyelination, serious infection with blunted fever and C-reactive protein.

Major interactions. Normalisation of CYP450 activity lowers levels of simvastatin, ciclosporin, warfarin, theophylline and oral contraceptives, so monitor for loss of effect when starting, and for toxicity when stopping. Other biologics (avoid) and live vaccines (avoid). Additive hepatotoxicity with methotrexate and other hepatotoxic drugs.

Common prescribing errors. Using C-reactive protein to judge infection; not checking neutrophils, platelets and ALT before each dose; inadvertent dosing over 800 mg intravenously.

Special groups.

• Pregnancy: limited data; use only where the benefit outweighs risk, and stop during the third trimester where possible.

• Breastfeeding: limited data; likely minimal transfer.

• Children: 8 to 12 mg/kg intravenously by weight and indication (2 years and over).

• Older adults: higher infection and perforation risk.

• Kidney impairment: no adjustment in mild to moderate; not studied in severe.

• Liver impairment: avoid in active hepatic disease or ALT over 1.5 times the upper limit of normal.

• Region: screen for tuberculosis, hepatitis B and HIV; in endemic areas maintain a high index of suspicion for infection despite normal C-reactive protein.

Formulations. Intravenous concentrate (dilute to 100 mL in 0.9 percent sodium chloride and infuse over 60 minutes, not as a bolus); 162 mg prefilled syringes or pens for subcutaneous use. Store at 2 to 8 degrees Celsius.

Baseline. Tuberculosis screen, hepatitis B and C and HIV serology, full blood count with differential, ALT, AST, lipid profile, and chest radiograph; exclude active diverticular disease where relevant.

Monitoring. Neutrophils, platelets and ALT at 4 to 8 weeks after starting, then every 3 months; lipids at 4 to 8 weeks then every 6 months.

Stop, hold or reduce thresholds.

• Neutrophils under 0.5 x 10^9/L: stop. Neutrophils 0.5 to 1.0 x 10^9/L: hold and restart at the lower dose once over 1.0.

• Platelets under 50 x 10^9/L: stop. Platelets 50 to 100 x 10^9/L: hold and restart at the lower dose once over 100.

• ALT over 1 to 3 times the upper limit of normal: reduce or hold. ALT over 5 times the upper limit of normal: stop.

• Serious infection or gastrointestinal perforation: stop.

Referral and escalation. Specialist initiated. Refer for unexplained abdominal pain, persistent neutropenia, or hepatotoxicity.