Introduction
Promacta (eltrombopag) is an oral thrombopoietin receptor agonist approved by the FDA in 2008. It represents a significant advancement in the management of thrombocytopenia by stimulating platelet production through a novel mechanism distinct from traditional therapies. This small molecule medication has transformed treatment paradigms for various hematologic conditions characterized by low platelet counts.
Mechanism of Action
Eltrombopag functions as a thrombopoietin (TPO) receptor agonist that binds to the transmembrane domain of the human TPO receptor. Unlike endogenous thrombopoietin, which binds to the extracellular domain, eltrombopag activates intracellular signaling pathways including JAK-STAT and MAPK, leading to increased proliferation and differentiation of megakaryocytes from bone marrow progenitor cells. This results in enhanced platelet production without stimulating platelet activation or aggregation directly.
Indications
- Chronic immune thrombocytopenia (ITP): Treatment of thrombocytopenia in patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy
- Hepatitis C-associated thrombocytopenia: Treatment of thrombocytopenia to allow initiation and maintenance of interferon-based therapy in patients with chronic hepatitis C
- Severe aplastic anemia: Treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy
- Other uses: Investigational uses include chemotherapy-induced thrombocytopenia and myelodysplastic syndromes
Dosage and Administration
Initial dosing:- ITP: 50 mg once daily (25 mg for patients of East Asian ancestry or those with hepatic impairment)
- Hepatitis C-associated thrombocytopenia: 25 mg once daily
- Severe aplastic anemia: 150 mg once daily (dose varies based on specific protocol)
- Take on an empty stomach (1 hour before or 2 hours after food)
- Avoid concomitant administration with polyvalent cations (antacids, dairy products, mineral supplements)
- Adjust dose based on platelet response with target range 50-200 × 10⁹/L
- Maximum dose: 75 mg daily for ITP and hepatitis C; 150 mg for aplastic anemia
- Hepatic impairment: Reduce initial dose
- Renal impairment: No adjustment needed for mild-to-moderate impairment
- Pediatric patients: FDA-approved for children ≥1 year with ITP
Pharmacokinetics
Absorption: Peak plasma concentrations achieved in 2-6 hours. Bioavailability significantly reduced with food, especially high-calcium meals. Distribution: >99% bound to plasma proteins. Apparent volume of distribution is approximately 52L. Metabolism: Primarily metabolized via cleavage, oxidation, and conjugation pathways. CYP1A2 and CYP2C8 are involved in oxidative metabolism. Elimination: Primarily fecal excretion (59%) with minor renal elimination (31%). Half-life is approximately 21-32 hours in healthy subjects and 26-35 hours in ITP patients.Contraindications
- Hypersensitivity to eltrombopag or any component of the formulation
- Use in combination with pegylated interferon/ribavirin in patients with chronic hepatitis C and hepatic decompensation (Child-Pugh Class B or C)
Warnings and Precautions
Hepatotoxicity: May cause hepatic enzyme elevations and bilirubin increases. Monitor liver function before initiation, every 2 weeks during dose adjustment, and monthly thereafter. Thrombotic/Thromboembolic Complications: Excessive platelet counts (>200 × 10⁹/L) may increase thrombotic risk. Dose reduction or interruption may be necessary. Bone Marrow Reticulin Formation and Fibrosis: May increase bone marrow reticulin fibers and collagen fibers. Monitor peripheral blood counts and peripheral smear. Cataracts: New onset or worsening of cataracts has been reported. Baseline and periodic ophthalmological examinations recommended. QTc Prolongation: May cause dose-related QTc prolongation. Use with caution in patients with congenital long QT syndrome or taking other QT-prolonging medications.Drug Interactions
Polyvalent Cation-Containing Products: Antacids, dairy products, and mineral supplements significantly reduce absorption. Separate administration by at least 4 hours. CYP Substrates: May increase exposure to drugs metabolized by CYP2C8 (e.g., repaglinide) and CYP1A2 (e.g., theophylline). Monitor closely. OATP1B1 Substrates: May increase exposure to rosuvastatin. Consider alternative statins or monitor for adverse effects.Adverse Effects
Common (≥10%):- Headache (15-28%)
- Fatigue (14-23%)
- Nausea (9-19%)
- Diarrhea (9-14%)
- Upper respiratory tract infection (10-12%)
- Elevated liver enzymes (5-13%)
- Hepatotoxicity (2-4%)
- Thrombotic events (3-7%)
- Bone marrow fibrosis (1-3%)
- Cataracts (5-9% in long-term studies)
Monitoring Parameters
- Platelet counts: Weekly until stable, then monthly
- Liver function tests: Baseline, every 2 weeks during dose adjustment, then monthly
- Peripheral blood smear: Baseline and periodically for morphological changes
- Ophthalmological examination: Baseline and annually
- ECG: In patients with cardiac risk factors or concomitant QT-prolonging medications
- Signs/symptoms of thrombosis: Especially in patients with risk factors
Patient Education
- Take medication on an empty stomach (1 hour before or 2 hours after food)
- Avoid taking with antacids, calcium supplements, or dairy products
- Report any signs of unusual bleeding or bruising
- Be aware of potential symptoms of blood clots (swelling, pain, redness in limbs)
- Regular blood tests are essential for safe treatment
- Inform all healthcare providers about Promacta use
- Use reliable contraception during treatment due to potential fetal risks
- Report any visual changes or eye symptoms promptly
References
1. FDA Prescribing Information: Promacta (eltrombopag). Revised 2023. 2. Bussel JB, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007;357(22):2237-2247. 3. Cheng G, et al. Eltrombopag for management of chronic immune thrombocytopenia (RAISE trial). Lancet. 2011;377(9763):393-402. 4. Townsley DM, et al. Eltrombopag added to standard immunosuppression for aplastic anemia. N Engl J Med. 2017;376(16):1540-1550. 5. McHutchison JG, et al. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med. 2007;357(22):2227-2236. 6. Clinical Pharmacology [Internet]. Tampa (FL): Gold Standard, Inc.; 2023 [cited 2023 Nov 15]. 7. Micromedex Solutions [Internet]. Greenwood Village (CO): Truven Health Analytics; 2023 [cited 2023 Nov 15].