Sarilumab

Sarilumab is a fully human monoclonal antibody against the interleukin 6 receptor, given subcutaneously every 2 weeks, used in rheumatoid arthritis after inadequate response to conventional drugs and in polymyalgia rheumatica after failure of glucocorticoids.

Class. Interleukin 6 receptor antagonist monoclonal antibody.

Mechanism. Binds membrane and soluble interleukin 6 receptors with high affinity, blocking interleukin 6 signalling.

Pharmacokinetics. Nonlinear, target-mediated clearance with half-life 8 to 10 days at the 200 mg dose. Steady state in about 14 to 16 weeks.

Rheumatoid arthritis (moderate to severe, after inadequate response).

• Dose: 200 mg subcutaneously every other week, alone or with methotrexate.

• Reduction: 150 mg every other week for neutropenia, thrombocytopenia or raised liver enzymes.

• Loading dose: none.

• Maximum dose: 200 mg every other week.

Polymyalgia rheumatica (after glucocorticoid failure or intolerance). 200 mg every other week with a tapering glucocorticoid course over 14 weeks; continue for up to 52 weeks.

Contraindications. Active serious infection including tuberculosis, and hypersensitivity.

Boxed-warning-level risks. Serious infections, including tuberculosis, invasive fungal, bacterial and viral infections.

Adverse effects. Common: neutropenia, raised ALT, injection site erythema, upper respiratory infection, urinary tract infection, hyperlipidaemia. Serious: serious infections, gastrointestinal perforation, thrombocytopenia, hepatotoxicity, anaphylaxis, demyelination.

Major interactions. Normalisation of CYP450 activity lowers levels of simvastatin, ciclosporin, warfarin and oral contraceptives; other biologics (avoid), live vaccines (avoid).

Common prescribing errors. Missing laboratory monitoring; not reducing the dose when counts fall; relying on fever and C-reactive protein to judge infection.

Special groups.

• Pregnancy: limited data; avoid unless benefit outweighs risk.

• Breastfeeding: limited data; avoid or use with caution.

• Children: not established for routine use.

• Older adults: higher infection risk; monitor.

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

• Liver impairment: not advised in active hepatic disease or with ALT over 1.5 times the upper limit of normal.

• Region: screen for tuberculosis, hepatitis B and HIV before starting.

Formulations. 150 mg and 200 mg prefilled syringes or pens, injected into the thigh or abdomen. Store at 2 to 8 degrees Celsius; may be kept at room temperature for up to 14 days.

Baseline. Tuberculosis screen, hepatitis B and C and HIV serology, neutrophils, platelets, ALT, lipids, and chest radiograph.

Monitoring. Neutrophils, platelets and ALT 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 150 mg once over 1.0 x 10^9/L.

• Platelets under 50 x 10^9/L: stop. Platelets 50 to 100 x 10^9/L: hold, restart at 150 mg once over 100.

• ALT over 1 to 3 times the upper limit of normal: reduce to 150 mg 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 persistent cytopenia, abdominal pain with fever, or serious infection.