Eltrombopag

Eltrombopag is an oral non-peptide thrombopoietin receptor agonist used for chronic immune thrombocytopenia, thrombocytopenia in chronic hepatitis C, and severe aplastic anaemia. It increases platelet counts over 1 to 2 weeks.

Classification. Thrombopoietin receptor agonist.

Mechanism. Binds the transmembrane domain of the thrombopoietin receptor, stimulating megakaryocyte proliferation and differentiation without competing with endogenous thrombopoietin.

Pharmacokinetics. Oral bioavailability is at least 52%, with peak levels at 2 to 6 hours. It is more than 99% protein bound and metabolised by hepatic cytochrome P450 enzymes (CYP1A2 and CYP2C8) and by glucuronidation. Half-life is about 21 to 32 hours. Exposure is 60 to 70% higher in people of East and South-East Asian ancestry.

Chronic immune thrombocytopenia (adults and children 1 year and over, after corticosteroids or immunoglobulin).

• Dose: 50 mg orally once daily in adults. Start at 25 mg in East or South-East Asian ancestry, any hepatic impairment, or children aged 1 to 5 years (25 mg); children aged 6 to 17 years start at 50 mg.
• Titration: adjust in 25 mg steps every 2 weeks to keep platelets at 50 to 150 × 10⁹/L. Reduce if platelets exceed 200 × 10⁹/L; interrupt above 400 × 10⁹/L and restart at a reduced dose when under 150 × 10⁹/L.
• Maximum: 75 mg daily. Stop after 4 weeks at 75 mg if platelets do not reach a level that prevents bleeding. Loading dose: none.

Thrombocytopenia in chronic hepatitis C (to allow interferon-based therapy).

• Dose: 25 mg orally daily, increased in 25 mg steps every 2 weeks to a maximum of 100 mg daily, to reach platelets of 90 × 10⁹/L or more.

Severe aplastic anaemia.

• First-line with immunosuppression (adults and children 12 years and over): 150 mg daily; 100 mg for ages 6 to 11; 75 mg for ages 2 to 5.
• Refractory: 50 mg daily (25 mg in East or South-East Asian ancestry or hepatic impairment), titrated every 2 weeks to a maximum of 150 mg daily; stop if there is no response by 16 weeks.

Adjustments. Kidney: no adjustment; use with care and monitor. Liver: start at 25 mg in chronic liver disease (Child-Pugh A to C), with 3 weeks between increases. Weight: no adjustment.

Contraindications. Hypersensitivity. When combined with interferon and ribavirin, the contraindications of those drugs also apply, including pregnancy.

Boxed-warning-level risk. Hepatotoxicity, and hepatic decompensation in chronic hepatitis C when used with interferon and ribavirin.

Warnings. Venous thromboembolism including portal vein thrombosis, cataract, rebound thrombocytopenia after stopping, bone marrow reticulin and clonal evolution in aplastic anaemia.

Adverse effects. Nausea, diarrhoea, headache, raised alanine aminotransferase, rash, cataract.

Interactions. Polyvalent cations (antacids, calcium-rich dairy, iron, magnesium, aluminium, zinc, selenium) reduce absorption; separate by at least 2 hours before or 4 hours after. Rosuvastatin exposure rises, so reduce its dose (start at 5 mg). Ciclosporin and lopinavir-ritonavir lower eltrombopag levels.

Pregnancy and breastfeeding. Avoid in pregnancy unless the benefit justifies the risk; avoid breastfeeding.

Common errors. Taking with calcium or iron; no liver tests; stopping suddenly; overlooking ancestry-based dose reduction. No adjustment is defined for African ancestry.

Administration. Oral, at least 2 hours before or 4 hours after calcium-rich food, dairy products or cation-containing preparations.

Baseline. Full blood count, liver function, blood film, eye examination for cataract in older patients.

Monitoring. Platelets weekly until stable on a dose for 4 weeks, then monthly. Liver function before starting, every 2 weeks during titration, and monthly after. Stop if alanine aminotransferase rises to 3 times the upper limit with progression, or with symptoms or bilirubin rise. After stopping, check platelets weekly for 4 weeks.

Referral and escalation. Refer thrombocytopenia unresponsive at 75 mg, new thrombosis, or liver injury to haematology or hepatology.