Everolimus

Everolimus is a 40-O-(2-hydroxyethyl) derivative of sirolimus with a shorter half-life, used in transplant rejection prophylaxis (with reduced exposure calcineurin inhibitor) and in oncology and tuberous sclerosis indications at different doses and products. The transplant and oncology products carry different strengths and are not interchangeable.

Class. mTOR inhibitor, proliferation signal inhibitor.

Mechanism. Binds FKBP12 and inhibits mTOR complex 1, blocking cytokine-driven T cell proliferation and angiogenic signalling.

Pharmacokinetics. Bioavailability about 30 percent, reduced by high fat meals. Metabolised by CYP3A4 and a P-glycoprotein substrate. Half-life about 28 to 30 hours, with steady state in about 4 days.

Kidney transplantation.

• Loading dose: none.

• Dose: 0.75 mg orally twice daily, started as soon as possible after transplant, with reduced dose ciclosporin and a glucocorticoid.

• Titration: adjust to a trough of 3 to 8 ng/mL, checking 4 to 5 days after each change.

• Maximum dose: no fixed ceiling; limited by trough.

Liver transplantation. 1 mg twice daily, started about 30 days after transplant, with reduced dose tacrolimus; trough 3 to 8 ng/mL.

Heart transplantation. 0.75 mg twice daily, with reduced dose ciclosporin; trough 3 to 8 ng/mL.

Oncology and tuberous sclerosis complex (specialist, different product). Usual oncology dose 10 mg once daily; tuberous sclerosis subependymal giant cell astrocytoma 4.5 mg/m2 once daily to a trough of 5 to 15 ng/mL; tuberous sclerosis seizures 5 mg/m2 once daily to a trough of 5 to 15 ng/mL.

Hepatic impairment (transplant). Reduce the dose by about one third in mild impairment (Child-Pugh A) and by one half in moderate impairment (Child-Pugh B); severe impairment, use only if benefit clearly outweighs risk and reduce further.

Contraindications. Hypersensitivity to everolimus, sirolimus or excipients.

Boxed-warning-level risks. Malignancies and serious infections, kidney graft thrombosis, nephrotoxicity when given with full dose ciclosporin, and increased mortality in heart transplantation in the first 3 months.

Adverse effects. Common: peripheral oedema, hyperlipidaemia, anaemia, mouth ulcers (stomatitis), constipation, hypertension, raised creatinine. Serious: pneumonitis, proteinuria, wound healing complications, thromboembolism, angioedema with ACE inhibitors, hyperglycaemia, infection.

Major interactions. Strong CYP3A4 or P-glycoprotein inhibitors (azole antifungals, clarithromycin, ritonavir; avoid) and inducers (rifampicin, carbamazepine, phenytoin, St John's wort), ciclosporin (higher dose raises nephrotoxicity), octreotide, ACE inhibitors, live vaccines (avoid), and grapefruit.

Common prescribing errors. Confusing transplant and oncology tablets; not reducing the calcineurin inhibitor dose; omitting level checks after interacting drugs.

Special groups.

• Pregnancy: avoid; contraception during treatment and for 8 weeks after stopping.

• Breastfeeding: avoid.

• Children: transplant use not established under 18 years in many regions; tuberous sclerosis dosing is body surface area based.

• Older adults: no adjustment; closer monitoring.

• Kidney impairment: no adjustment; follow proteinuria and creatinine.

• Liver impairment: reduce the dose by about one third in mild and one half in moderate impairment.

• Region: trough monitoring availability and tuberculosis, hepatitis B and HIV screening matter before starting.

Formulations. 0.25, 0.5, 0.75 and 1 mg tablets for transplant; 2.5, 5 and 10 mg tablets and dispersible tablets for oncology and tuberous sclerosis. Take twice daily at fixed times, consistently with or without food, together with the calcineurin inhibitor.

Baseline. Full blood count, creatinine, lipids, liver enzymes, urine protein to creatinine ratio, glucose, and infection screening.

Monitoring. Trough 4 to 5 days after starting or any dose or interacting drug change, then at least monthly early. Lipids, full blood count, creatinine, urine protein and glucose at each visit.

Stop or switch thresholds. Non-infectious pneumonitis; sustained heavy proteinuria; graft thrombosis; severe wound dehiscence; thrombotic microangiopathy.

Referral and escalation. Always specialist initiated. Refer for new respiratory symptoms, rising proteinuria, or trough outside target.