ETP

Approved Indications:

• Chronic Immune (Idiopathic) Thrombocytopenia (ITP):
• In adults and pediatric patients ≥1 year who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
• Thrombocytopenia in Hepatitis C Virus (HCV)-related Chronic Liver Disease:
• To allow initiation and maintenance of interferon-based therapy in adult patients.
• Severe Aplastic Anemia (SAA):
• In adult and pediatric patients ≥2 years:
• Refractory to prior immunosuppressive therapy.
• First-line treatment in combination with standard immunosuppressive therapy (e.g., horse antithymocyte globulin + cyclosporine).

Route of Administration:

• Oral; tablets should be taken on an empty stomach or at least 2 hours before or 4 hours after meals containing calcium, dairy, or polyvalent cations.

A. Chronic ITP:

• Adults:
• Initial dose: 50 mg once daily
• East Asian patients: Start at 25 mg once daily
• Dose range: 25–75 mg daily
• Adjust based on platelet response; discontinue if no response after 4 weeks of 75 mg/day
• Pediatric Patients (≥1 year):
• Start: 25 mg once daily
• Adjust based on platelet count; maximum: 75 mg/day

B. HCV-associated Thrombocytopenia:

• Adults:
• Initial dose: 25 mg once daily
• Titrate every 2 weeks to a maximum of 100 mg/day
• Discontinue if platelet count does not increase to ≥50,000/mm³ after 2 weeks at 100 mg

C. Severe Aplastic Anemia:

• Refractory Cases:
• Initial dose: 50 mg once daily
• Pediatric: 2.5 mg/kg (age 2–5 years), 75 mg (age ≥6 years)
• Adjust based on platelet count; discontinue if no response after 16 weeks
• First-line (combination):
• 150 mg once daily in adults (in combination with immunosuppressants)
• Pediatric dose adjusted by age/weight

Renal Impairment:

• No dose adjustment required; monitor platelet count and renal function.

Hepatic Impairment:

• Mild: No initial dose adjustment
• Moderate to Severe: Start at 25 mg once daily; use caution, monitor closely
• Contraindicated in severe hepatic impairment when used for HCV-related thrombocytopenia

Eltrombopag is a small-molecule thrombopoietin receptor (TPO-R) agonist that binds to the transmembrane domain of the TPO receptor (c-Mpl) on hematopoietic stem and progenitor cells. It activates the JAK/STAT signaling pathway, promoting proliferation and differentiation of megakaryocytes, leading to increased platelet production. Unlike endogenous thrombopoietin, it binds at a distinct site, avoiding neutralization by autoantibodies in immune-mediated conditions. In severe aplastic anemia, it also stimulates trilineage hematopoiesis (platelets, red cells, neutrophils) through hematopoietic stem cell expansion.

• Absorption:
• Tmax ~2–6 hours
• Decreased bioavailability with polyvalent cations (calcium, magnesium, iron)
• Bioavailability:
• ~52% (oral)
• Food (especially dairy) reduces absorption by ~59%
• Distribution:
• Volume of distribution: ~151 L
• Plasma protein binding: ~99.8% (mainly to albumin)
• Metabolism:
• Metabolized in liver via CYP1A2, CYP2C8, and UGT1A1
• Also metabolized by non-CYP mechanisms
• Elimination:
• Half-life: ~21–32 hours
• Excreted via feces (59%) and urine (31%) as metabolites

• Pregnancy:
• FDA Pregnancy Category Not Assigned
• Animal studies showed embryo-fetal toxicity at high doses
• Use only if clearly needed and benefits outweigh risks
• Not recommended during pregnancy unless under strict specialist supervision
• Lactation:
• Unknown if excreted in human milk
• Due to potential adverse effects on infants, avoid breastfeeding or discontinue drug
• Fertility:
• Reversible impairment of fertility observed in animal studies at high doses

• Primary Class: Hematopoietic Agent
• Subclass: Thrombopoietin Receptor Agonist (TPO-RA)
• Generation: First-generation non-peptide oral TPO-R agonist

• Known hypersensitivity to eltrombopag or excipients
• Severe hepatic impairment when treating HCV-associated thrombocytopenia
• Concurrent use with products containing polyvalent cations (relative contraindication)
• Active thromboembolic disease (use with caution)

• Hepatotoxicity:
• Elevation of liver enzymes (ALT, AST, bilirubin); monitor LFTs regularly
• Discontinue if liver function worsens significantly
• Thromboembolic Events:
• Increased risk, especially with excessive platelet elevation (>400,000/mm³)
• Use lowest effective dose; monitor platelets weekly until stable
• Cataracts:
• Risk of posterior subcapsular cataracts; periodic eye exams recommended
• Bone Marrow Fibrosis:
• Risk of reticulin fiber deposition; monitor with bone marrow biopsies if clinically indicated
• Hematologic Malignancy Risk:
• Theoretical risk due to stimulation of hematopoietic progenitors
• Iron Chelation:
• Eltrombopag chelates iron; monitor ferritin and iron levels during therapy
• Loss of Response After Discontinuation:
• Rapid decline in platelet counts upon stopping; risk of bleeding

Common (≥10%):

• Hepatic: Elevated ALT, AST, bilirubin
• GI: Nausea, diarrhea
• General: Fatigue, headache
• Hematologic: Increased platelet count, potential rebound thrombocytopenia on withdrawal

Less Common (1–10%):

• Cataracts
• Thromboembolic events (DVT, pulmonary embolism)
• Myalgia, back pain
• Dry mouth

Serious/Rare:

• Hepatotoxicity and liver failure
• Bone marrow fibrosis
• Aplastic anemia relapse
• Severe bleeding after abrupt withdrawal

Timing:

• Most side effects appear within the first 1–2 months; dose-related and reversible upon discontinuation

• Polyvalent Cations (calcium, magnesium, aluminum, iron):
• Significantly reduce absorption; separate administration by at least 4 hours
• Statins (rosuvastatin, simvastatin):
• Increased exposure due to BCRP inhibition; monitor for toxicity
• Cyclosporine:
• Increases eltrombopag concentration via BCRP inhibition; monitor platelet counts and liver enzymes
• Rifampin:
• Induces UGT1A1 and CYP enzymes; may reduce efficacy
• Enzyme Systems:
• Substrate for CYP1A2, CYP2C8, UGT1A1
• Inhibits BCRP and OATP1B1

• Severe Aplastic Anemia (SAA):
• Now approved as first-line therapy in combination with standard immunosuppressive regimens
• Updated inclusion in hematology guidelines (e.g., NIH, ASH) for treatment-refractory SAA
• Labeling Updates:
• Expanded indications to include pediatric patients
• Updated warnings on hepatotoxicity and thromboembolic events
• Pharmacogenomic Considerations:
• Genetic variations (e.g., OATP1B1 polymorphisms) may affect drug exposure

• Temperature:
• Store at 20°C to 25°C (68°F to 77°F)
• Excursions permitted between 15°C and 30°C (59°F and 86°F)
• Humidity & Light:
• Protect from moisture; keep tablets in original container
• No special light protection required
• Handling Precautions:
• Keep out of reach of children
• Do not use if tablets are damaged or past expiration date
• No refrigeration or reconstitution required