Safety Analysis of Romiplostim, Eltrombopag, and Avatrombopag Post-market Approval: a Pharmacovigilance Study Based on the FDA Adverse Event Reporting System

Overview

Journal BMC Pharmacol Toxicol

Publisher Biomed Central

Specialty Pharmacology

Date 2025 Feb 27

PMID 40016824

Authors

Xiaoling Wang

Yunsong Li

Wei Zhuang

Affiliations

Soon will be listed here.

Abstract

Background: Romiplostim, eltrombopag, and avatrombopag, as new-generation thrombopoietin receptor agonists (TPO-RAs), have been widely used in the treatment of immune thrombocytopenia (ITP). Given their similar efficacy, a comprehensive evaluation of their safety is crucial for optimizing treatment choices. This study aims to explore the potential safety issues of three major drugs for treating ITP: romiplostim, eltrombopag, and avatrombopag, thereby providing references and research directions for subsequent high-quality clinical studies.

Methods: We retrieved data from the FDA Adverse Event Reporting System (FAERS) database from the first quarter of 2018 to the second quarter of 2023. Using reporting odds ratio (ROR), proportional reporting ratio (PRR), bayesian confidence propagation neural network (BCPNN), and multiple gamma poisson shrinkage (MGPS), we mined and analyzed adverse events (AEs) associated with romiplostim, eltrombopag, and avatrombopag. The Designated Medical Event (DME) list from the European Medicines Agency (EMA) was used to screen out the DME of three drugs. Venn analysis was used to screen the specific AEs of each drug.

Results: The study included 2,851 cases of romiplostim, 10,297 cases of eltrombopag, and 973 cases of avatrombopag. Venn analysis revealed nine common AEs across the three drugs. The number of significant specific AEs associated with romiplostim, eltrombopag, and avatrombopag were 58, 98, and 15 respectively. DMEs for romiplostim included autoimmune haemolytic anaemia (ROR = 6.1, n = 3), haemolytic anaemia (ROR = 8.13, n = 7), sudden hearing loss (ROR = 5.24, n = 3), haemolysis (ROR = 3.89, n = 3). DMEs for eltrombopag included hepatic infection (ROR = 9.56, n = 6), granulocytopenia (ROR = 2.91, n = 4), autoimmune haemolytic anaemia (ROR = 3.03, n = 5), haemolytic anaemia (ROR = 3.46, n = 10), haemolysis (ROR = 4.65, n = 12), hepatic failure (ROR = 2.51, n = 23). Not a single DME was found for avatrombopag.

Conclusion: This study indicates that eltrombopag manifests significant safety signals within the hepatic system. This implies that monitoring liver function during treatment is advisable. Avatrombopag shows relatively lower hepatotoxicity signals; however, further large-scale studies are needed to validate these observations. Moreover, both romiplostim and eltrombopag therapies may be linked to a risk of sudden hearing loss or deafness, which merits clinical attention. These findings offer crucial safety references for clinical drug use. Nevertheless, the causal relationship between the drugs and AEs necessitates further in-depth investigation.

References

Tarantino M, Bussel J, Lee E, Jamieson B . A phase 3, randomized, double-blind, active-controlled trial evaluating efficacy and safety of avatrombopag versus eltrombopag in ITP. Br J Haematol. 2023; 202(4):897-899. DOI: 10.1111/bjh.18908. View

Douglas V, Tallman M, Cripe L, Peterson L . Thrombopoietin administered during induction chemotherapy to patients with acute myeloid leukemia induces transient morphologic changes that may resemble chronic myeloproliferative disorders. Am J Clin Pathol. 2002; 117(6):844-50. DOI: 10.1309/09NP-3DFG-BLM9-E5LE. View

Neunert C, Terrell D, Arnold D, Buchanan G, Cines D, Cooper N . American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019; 3(23):3829-3866. PMC: 6963252. DOI: 10.1182/bloodadvances.2019000966. View

Marano M, Serafinelli J, Cairoli S, Martinelli D, Pisani M, Palumbo G . Eltrombopag-Induced Acute Liver Failure in a Pediatric Patient: A Pharmacokinetic and Pharmacogenetic Analysis. Ther Drug Monit. 2018; 40(4):386-388. DOI: 10.1097/FTD.0000000000000522. View

Ghanima W, Geyer J, Lee C, Boiocchi L, Imahiyerobo A, Orazi A . Bone marrow fibrosis in 66 patients with immune thrombocytopenia treated with thrombopoietin-receptor agonists: a single-center, long-term follow-up. Haematologica. 2014; 99(5):937-44. PMC: 4008112. DOI: 10.3324/haematol.2013.098921. View

Bussel J, Garcia de Miguel P, Despotovic J, Grainger J, Sevilla J, Blanchette V . Eltrombopag for the treatment of children with persistent and chronic immune thrombocytopenia (PETIT): a randomised, multicentre, placebo-controlled study. Lancet Haematol. 2015; 2(8):e315-25. DOI: 10.1016/S2352-3026(15)00114-3. View

Seger D, Barker K, McNaughton C . Misuse of the Naranjo Adverse Drug Reaction Probability Scale in toxicology. Clin Toxicol (Phila). 2013; 51(6):461-6. PMC: 3887443. DOI: 10.3109/15563650.2013.811588. View

Saleh M, Bussel J, Cheng G, Meyer O, Bailey C, Arning M . Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood. 2012; 121(3):537-45. DOI: 10.1182/blood-2012-04-425512. View

Al-Samkari H, Jiang D, Gernsheimer T, Liebman H, Lee S, Wojdyla M . Adults with immune thrombocytopenia who switched to avatrombopag following prior treatment with eltrombopag or romiplostim: A multicentre US study. Br J Haematol. 2022; 197(3):359-366. PMC: 9306832. DOI: 10.1111/bjh.18081. View

10.

Noguchi Y, Tachi T, Teramachi H . Detection algorithms and attentive points of safety signal using spontaneous reporting systems as a clinical data source. Brief Bioinform. 2021; 22(6). DOI: 10.1093/bib/bbab347. View

11.

Cheng G, Saleh M, Marcher C, Vasey S, Mayer B, Aivado M . Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2010; 377(9763):393-402. DOI: 10.1016/S0140-6736(10)60959-2. View

12.

Jones A, Sapatnekar S, Bakdash S . Drugs and Conditions That May Mimic Hemolysis. Am J Clin Pathol. 2022; 159(1):34-42. DOI: 10.1093/ajcp/aqac130. View

13.

Fang Q, Huang F, Liang J, Chen Y, Li C, Zhang M . Safety of romiplostim and eltrombopag for children with immune thrombocytopenia: a pharmacovigilance study of the FDA adverse event reporting system database. Expert Opin Drug Saf. 2023; 22(8):707-714. DOI: 10.1080/14740338.2023.2182288. View

14.

Evangelista M, Amadori S, Stasi R . Biologic aspects of thrombopoietin and the development of novel thrombopoietic agents for clinical use. Curr Drug Discov Technol. 2007; 4(3):162-73. DOI: 10.2174/157016307782109698. View

15.

Brynes R, Wong R, Thein M, Bakshi K, Burgess P, Theodore D . A 2-Year, Longitudinal, Prospective Study of the Effects of Eltrombopag on Bone Marrow in Patients with Chronic Immune Thrombocytopenia. Acta Haematol. 2016; 137(2):66-72. DOI: 10.1159/000452992. View

16.

Bussel J, Kulasekararaj A, Cooper N, Verma A, Steidl U, Semple J . Mechanisms and therapeutic prospects of thrombopoietin receptor agonists. Semin Hematol. 2019; 56(4):262-278. DOI: 10.1053/j.seminhematol.2019.09.001. View

17.

Al-Samkari H, Goodarzi K . An Eltrombopag Red (Plasma) Alert. Acta Haematol. 2020; 144(2):227-228. DOI: 10.1159/000508599. View

18.

Corman S, Mohammad R . Eltrombopag: a novel oral thrombopoietin receptor agonist. Ann Pharmacother. 2010; 44(6):1072-9. DOI: 10.1345/aph.1P042. View

19.

Wong R, Saleh M, Khelif A, Salama A, Portella M, Burgess P . Safety and efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: final results of the EXTEND study. Blood. 2017; 130(23):2527-2536. DOI: 10.1182/blood-2017-04-748707. View

20.

Mohammed S, Shab-Bidar S, Abuzerr S, Habtewold T, Alizadeh S, Djafarian K . Association of anemia with sensorineural hearing loss: a systematic review and meta-analysis. BMC Res Notes. 2019; 12(1):283. PMC: 6533653. DOI: 10.1186/s13104-019-4323-z. View