Postmarketing safety of eltrombopag olamine : an analysis of the FDA Adverse Event Reporting System (FAERS)

doi:10.21203/rs.3.rs-5236894/v1

Objective This study aims to investigate the risk factors associated with adverse events related to the novel thrombopoietin receptor agonist, eltrombopag olamine, with the intention of providing guidance for safe clinical medication practices.

Methods Adverse drug event (ADE) reports from the US Food and Drug Administration's Adverse Event Reporting System (FAERS) spanning from the first quarter of 2004 to the third quarter of 2023 were collected and subjected to statistical analysis based on the System Organ Classification (SOC) and Preferred Terms (PT) as defined by the International Dictionary of Medical Terms (MedDRA). The report ratio method (ROR) and the proportional report ratio method (PRR) were used.

Results A total of 10,357 adverse drug reaction (ADR) reports, with eltrombopag olamine identified as the primary suspected drug, were retrieved from the FAERS database. These reports included 228 risk signals at the Preferred Term (PT) level and 22 signals overall. The three most frequently reported adverse events were decreased platelet count, death and increased platelet count. The three adverse events with the highest signal intensity were increased reticulin, reticular fibrosis of bone marrow and leukopenia, respectively.Among the adverse reactions not specified in the instruction manual for eltrombopag olamine are ascites associated with gastrointestinal diseases, blistering of the oral mucosa, iron deficiency, and emaciation related to metabolic and nutritional disorders, as well as Alzheimer's dementia among various nervous system diseases, and other signals. There is no conclusive evidence to dismiss a correlation with eltrombopag olamine. The primary risks associated with SMQ drugs include hematopoietic cytopenia, various forms of bleeding, embolism, and thrombosis.

Conclusion Eltrombopag olamine has been demonstrated to be safe, with the majority of prominent risk signals aligning with known adverse reactions associated with the blood and lymphatic systems, as outlined in the prescribing information. It is recommended that clinicians exercise caution regarding the potential risks of paroxysmal nocturnal hemoglobinuria, abnormal platelet counts, hemorrhage, and hearing loss when administering eltrombopag olamine in a clinical setting.

Eltrombopag olamine

Adverse drug events

FAERS database

Data mining

Eltrombopag olamine, a non-peptide thrombopoietin receptor agonist (TPO-RA), represents the first oral pharmacological intervention globally approved for the treatment of chronic immune thrombocytopenia (ITP) in patients unresponsive to conventional therapies^[1]. Beyond its application in ITP, eltrombopag olamine tablets have received approval in the United States for the management of thrombocytopenia associated with chronic liver disease and for the treatment of aplastic anemia^[2].In December 2017, eltrombopag olamine tablets were introduced in China for the treatment of immune thrombocytopenia (ITP) and severe aplastic anemia (SAA) in patients aged 6-11 and over 18 who have not responded to prior glucocorticoid and immunoglobulin therapies^[3-4]. According to the drug's prescribing information, common adverse reactions include headache, anemia, upper respiratory tract infection, and insomnia^[5-7]. Currently, there are single-center studies and case reports in the literature regarding adverse drug events (ADEs) associated with eltrombopag olamine; however, the sample sizes in these studies are limited^[8-9].In this study, the adverse drug event (ADE) signal associated with etoposepa ethanolamine was analyzed by mining data from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. The objective was to provide a foundation for the safe and rational clinical use of this drug.

2.1. Data source

According to the data of FAERS, this study used the online OpenVigil retrieval tool^[10] to retrieve ADE named "eltrombopag olamine" from the first quarter of 2004 to the third quarter of 2023 in FAERS database.

2.2. Data extraction and analysis

In this study, signal mining adopts the reporting odds ratio (ROR) method and the proportional reporting ratio (PRR) method. These two methods compare the target ADE incidence of the target drug with the target ADE incidence of all other drugs. If the ratio is greater than the set threshold, it is called imbalance, suggesting that a potential ADE signals has been generated. These two research methods are all four-grid tables based on the proportional imbalance method (Table 1). According to the formula, the ROR value, PRR value and the corresponding 95% confidence interval (95% CI) are calculated, and the signal is filtered according to the set threshold. The calculation formulas and thresholds of the ROR method and the PRR method are shown in Table 2.The signal generation standard of the ROR method is as follows: the reported number (a) is ≥3, and the lower limit of the 95% CI of the ROR value is＞1, which indicates that the signal is generated;The signal generation standard of the PRR method is: the number of reports (a)≥3, and the lower limit of 95% CI of PRR value＞1 indicates that a signal is generated. The larger the lower limit of the 95% CI is, the stronger the signal is, that is, the stronger the connection between the target drug and the target ADE.The larger the lower limit of the 95% CI is, the stronger the signal is, that is, the stronger the connection between the target drug and the target ADE. The two methods have high reliability and sensitivity, and the number of false positive signals can be reduced by combining them. The classification analysis of Medical Management Activity Dictionary (MedDRA) and standard MedDRA analysis query (SMQ) were used to analyze the risk signals of serious adverse drug reactions (ADR) of Eltrombopag olamine. The statistical analysis softwares used in this study are SPSS 20.0 and Microsoft Excel 2016.

3.1. Basic characteristics of Brexpiprazole-related ADEs

According to the above criteria, 10 357 ADE reports involving 228 ADE cases were retrieved from the FAERS database. Women accounted for 51.14% of the informants, patients aged 18-64 account for 20.18%, and consumers accounted for 56.37% of the informants. See Table 3 for the basic information of ADE report related to Eltrombopag olamine.

Table 3 Basic information on ADEs related to Brexpiprazole from the FAERS database.
Factors	Number of events (%)
Gender
Male	4268(41.21)
Female	5297(51.14)
Unknown	792(7.65)
Age
0-2	176(0.17)
3-17	254(2.45)
18-64	2090(20.18)
65-85	1976(19.08)
≥85	351(3.39)
Unknown	5669(54.74)
Reporter
Professional medical staff	4329(41.8)
Consumer	5838(56.37)
Unknown	188(1.82)

3.2. ADE report and signal mining for SOC of Eltrombopag olamine.

According to the set threshold, the ROR and PRR methods are used to mine signals, and 228 ADE signals involving 22 SoC are obtained. The results showed that the top three cases reported by ADE were platelet count decreased (1974 cases), death 1 831 cases) and platelet count increased (546 cases) (Table 4). According to the signal intensity reported by ADE, the top three are reticulin increased (30 cases), bone marrow reticulin fibrosis (6 cases) and leukoerythroblastic anaemia (3 cases) (Table 5). The top three SOC of ADE cases are: investigations (3 472 cases, 48 cases of PT), general disorders and administration site conditions (2 421 cases, 15 cases of PT), and blood and lymphatic system disorders (798 cases, 26 cases of PT) (Table 6).

Table 4 The top 20 frequency preference (PT) of adverse events of Eltrombopag olamine ranked in the FAERS database.
	PT	DE	ROR(95%CI)	PRR()
1	Platelet count decreased	1974	56.625（53.872~59.519）	46.023（83866.58）
2	Death	1831	4.397（4.181~4.625）	3.797（3940.754）
3	Platelet count increased	546	111.142（101.586~121.596）	105.335（51556.242）
4	Product use in unapproved indication	319	3.196（2.858~3.573）	3.128（463.072）
5	Hemorrhage	230	4.654（4.083~5.306）	4.573（639.112）
6	Haemoglobin decreased	202	5.047（4.39~5.803）	4.968（635.994）
7	Thrombocytopaenia	180	4.069（3.511~4.717）	4.016（405.008）
8	Contusion	179	4.642（4.003~5.383）	4.579（497.081）
9	Platelet count abnormal	173	68.818（58.958~80.326）	67.685（10664.832）
10	Thrombosis	148	3.732（3.173~4.391）	3.693（288.188）
11	Epistaxis	135	4.28（3.611~5.074）	4.237（330.473）
12	Petechiae	132	32.273（27.117~38.409）	31.874（3811.011）
13	Illness	127	3.584（3.008~4.271）	3.553（230.472）
14	Disease progression	125	2.207（1.849~2.633）	2.192（80.126）
15	Immune thrombocytopenia	119	30.764（25.617~36.945）	30.422（3270.168）
16	Pulmonary embolism	109	2.36（1.954~2.85）	2.345（82.985）
17	Hypoacusis	106	4.236（3.497~5.131）	4.203（255.214）
18	Covid-19	101	2.754（2.263~3.351）	2.737（109.73）
19	Sepsis	101	2.273（1.868~2.766）	2.261（69.907）
20	General physical health deterioration	98	2.313（1.895~2.823）	2.301（70.907）

Abbreviations: - PT:preferred terms, DE: Case reports, ROR: Reporting odds ratio, PRR: Proportional reporting ratio,CI: Confidence interval, χ2:chi-square.

Table 5 The top 20 signal strength of adverse events of Eltrombopag olamine ranked at the PTs level in the FAERS database.
	PT	DE	ROR(95%CI)	PRR()
1	Reticulin increased	6	339.873（136.461~846.497）	339.677（1308.68）
2	Bone marrow reticulin fibrosis	30	264.077（177.415~393.072）	263.315（6149.267）
3	Leukoerythroblastic anaemia	3	161.797（48.253~542.527）	161.751（290.397）
4	Platelet count increased	546	111.142（101.586~121.596）	105.335（51556.242）
5	Clonal evolution	4	96.399（34.725~267.61）	96.362（265.484）
6	Paroxysmal nocturnal haemoglobinuria	10	79.254（41.732~150.515）	79.179（650.19）
7	Blast cell proliferation	3	79.017（24.51~254.739）	78.995（149.148）
8	Labelled drug-food interaction issue	4	78.116（28.355~215.21）	78.087（217.157）
9	Labelled drug-food interaction medication error	20	77.171（49.042~121.434）	77.024（1334.849）
10	Platelet count abnormal	173	68.818（58.958~80.326）	67.685（10664.832）
11	Nucleated red cells	3	64.108（20.03~205.188）	64.09（121.637）
12	Myelofibrosis	76	55.74（44.24~70.23）	55.339（3814.999）
13	Platelet disorder	56	48.181（36.851~62.996）	47.926（2423.976）
14	Platelet count decreased	1974	56.625（53.872~59.519）	46.023（83866.58）
15	Bone marrow myelogram abnormal	3	45.915（14.474~145.66）	45.902（87.13）
16	Anaemia aplastic aregenerative	95	46.305（37.683~56.899）	45.889（3966.824）
17	Aspiration bone marrow abnormal	3	44.126（13.922~139.862）	44.114（83.681）
18	Megakaryocytes increased	3	43.561（13.747~138.031）	43.548（82.588）
19	Hepatic infection	19	36.59（23.162~57.802）	36.524（602.021）
20	Petechiae	132	32.273（27.117~38.409）	31.874（3811.011）

Abbreviations: - PT:preferred terms, DE: Case reports, ROR: Reporting odds ratio, PRR: Proportional reporting ratio,CI: Confidence interval, χ2:chi-square.

Table 6 Main ADE signal of Eltrombopag olamineand its involvement in SOC.
SCO	Signal number	DE	Major PT（Top3）	n	ROR(95%CI)	PRR()
Investigations	48	3472	Platelet count decreased	1974	56.625（53.872~59.519）	46.023（83866.58）
			Platelet count increased	546	111.142（101.586~121.596）	105.335（51556.242）
			Haemoglobin decreased	202	5.047（4.39~5.803）	4.968（635.994）
General disorders and administration site conditions	15	2421	Death	1831	4.397（4.181~4.625）	3.797（3940.754）
			Illness	127	3.584（3.008~4.271）	3.553（230.472）
			Disease progression	125	2.207（1.849~2.633）	2.192（80.126）
Blood and lymphatic system disorders	26	798	Thrombocytopenia	180	4.069（3.511~4.717）	4.016（405.008）
			Immune thrombocytopenia	119	30.764（25.617~36.945）	30.422（3270.168）
			Anaemia aplastic aregenerative	95	46.305（37.683~56.899）	45.889（3966.824）
Vascular disorders	18	664	Haemorrhage	230	4.654（4.083~5.306）	4.573（639.112）
			Thrombosis	148	3.732（3.173~4.391）	3.693（288.188）
			Deep thrombophlebitis	80	2.478（1.988~3.088）	2.466（68.357）
Injury, poisoning and procedural complications	6	554	Product use in unapproved indication	319	3.196（2.858~3.573）	3.128（463.072）
			Contusion	179	4.642（4.003~5.383）	4.579（497.081）
			Broken hip	29	2.055（1.427~2.959）	2.052（14.595）
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	21	382	Myelodysplastic syndrome	82	12.702（10.209~15.804）	12.61（855.931）
			Myelofibrosis	76	55.74（44.24~70.23）	55.339（3814.999）
			Acute myeloid leukaemia	54	7.747（5.924~10.132）	7.712（306.895）
Hepatobiliary disorders	14	351	Liver disorder	91	4.607（3.746~5.665）	4.575（250.113）
			Icterus	39	3.191（2.329~4.371）	3.182（56.111）
			Failure liver	37	2.661（3.676~1.926）	2.655（36.502）
Infections and infestations	10	298	Novel COVID-19-infected pneumonia	101	2.754（2.263~3.351）	2.737（109.73）
			Pyemia	101	2.273（1.868~2.766）	2.261（69.907）
			Infection viral	33	2.576（3.627~1.83）	2.571（30.104）
Respiratory, thoracic and mediastinal disorders	4	268	Epistaxis	135	4.28（3.611~5.074）	4.237（330.473）
			Embolism pulmonary	109	2.36（1.954~2.85）	2.345（82.985）
			Pulmonary thrombosis	17	3.56（2.211~5.733）	3.556（28.649）
Skin and subcutaneous tissue disorders	8	245	Petechiae	132	32.273（27.117~38.409）	31.874（3811.011）
			Decoloration skin	41	2.235（1.644~3.039）	2.23（26.608）
			Purpura	19	5.479（3.49~8.603）	5.471（64.732）

Abbreviations: - SOC:System organ class, DE: Case reports, PT=Preferred term, n=number of adverse events, ROR: Reporting odds ratio, PRR: Proportional reporting ratio,CI: Confidence interval, χ2:chi-square.

3.3. ADE report and signal mining for SMQ of Eltrombopag olamine.

According to the SMQ catalogue in MedDRA and the narrow and broad definition standard of AE, 228 kinds of AE are divided into 75 SMQs. Most SMQ is mainly AE in narrow sense.According to the search of stenosis, the top five SMQ are haematopoietic erythropenia (2154 cases), haemorrhage laboratory terms (excl laboratory terms) (1053 cases), embolic and thrombotic events, vessel type unspecified and mixed arterial and venous (303 cases), embolic and thrombotic events, venous(287 cases) and liver related investigations, signs and symptoms (248 cases) (Table 7). The top five generalized SMQ are drug reaction with eosinophilia and systemic symptoms syndrome (3018 cases), haematopoietic thrombocytopenia (2383 cases), systemic lupus erythematosus(2303 cases), haemorrhage terms (excl laboratory terms) (1171 cases) and immune-mediated/autoimmune disorders (491 cases) (Table 8).

Table 7 Main ADE signal of Eltrombopag olamineand its involvement in narrow classification of SMQ.
SMQ	Signal number	DE	Major PT（Top3）	n
Haematopoietic erythropenia	2	2154	Platelet count decreased	1974
			Thrombocytopaenia	180
Haemorrhage laboratory terms (excl laboratory terms)	24	1053	Hemorrhage	230
			Contusion	179
			Silt point	132
Embolic and thrombotic events, vessel type unspecified and mixed arterial and venous	13	303	Thrombosis	148
			Cerebral infarct	68
			Embolism	23
			Anaemia aplastic aregenerative	95
Embolic and thrombotic events, venous	12	287	Embolism pulmonary	109
			Deep thrombophlebitis	80
			Portal vein thrombosis	23
Liver related investigations, signs and symptoms	11	248	Elevated liver enzymes	66
			Blood bilirubin increased	54
			Function liver abnormal	37

Abbreviations: - SMQ:Standard MedDRA analysis query, DE: Case reports, n=number of adverse events.

Table 8 Main ADE signal of Eltrombopag olamineand its involvement in generalized classification of SMQ.
SMQ	Signal number	DE	Major PT（Top3）	n
Drug reaction with eosinophilia and systemic symptoms syndrome	36	3018	Platelet count decreased	1974
			Thrombocytopaenia	180
			Immune thrombocytopenia	119
Haematopoietic thrombocytopenia	4	2383	Platelet count decreased	1974
			Thrombocytopaenia	180
			Platelet count abnormal	173
Systemic lupus erythematosus	6	2303	Platelet count decreased	1974
			Thrombocytopaenia	180
			Immune thrombocytopenia	119
Haemorrhage terms (excl laboratory terms)	22	1171	Haemorrhage	230
			Contusion	179
			Epistaxis	135
Immune-mediated/autoimmune disorders	10	491	Thrombocytopaenia	180
			Immune thrombocytopenia	119
			Anaemia aplastic	95

Abbreviations: - SMQ:Standard MedDRA analysis query, DE: Case reports, n=number of adverse events.

In this study, a total of 10 357 ADE signals were analyzed, encompassing 228 risk signals at the PT level, distributed across 22 SOCs and 75 SMQs. High-frequency and strong ADE signals identified include decreased platelet count, mortality, increased platelet count, petechiae, and immune thrombocytopenia, among others. These findings are consistent with common ADEs reported in drug labeling and previous literature, primarily related to the pharmacological effects of the drugs studied^{[5, 12-13]}. This congruence substantiates the reliability of the present study.However, the adverse reactions identified in clinical trials are subject to certain limitations, including stringent trial designs, specific inclusion criteria, and relatively small sample sizes. Consequently, the data derived from these trials may not be generalizable to real-world scenarios, where patient indications and complications vary^[14]. To address these limitations, we conducted a comprehensive analysis of ethanolamine ADRs associated with Etroppa using the FAERS database. This approach provides a more systematic and exhaustive assessment compared to previously reported studies^[4-6].

The findings of this study indicate the presence of numerous potential ADE signals within diseases of the blood and lymphatic system, as well as vascular and lymphatic diseases classified under the SOC. The frequency of reports and the intensity of these signals are notably high. Clinical trials have demonstrated that adverse reactions such as bleeding and thrombocytopenia induced by etoposethanolamine are correlated with the patient's baseline platelet count, with the highest probability of severe bleeding occurring in patients with platelet counts below 20 000/mm³^[12]. Furthermore, the risk of bleeding and thrombocytopenia is comparatively higher in pediatric patients than in adults^[15-16], so children should assess the risks and benefits when using eltrombopag olamine. Clinical studies involving patients with relapsed/refractory immune thrombocytopenia have demonstrated that eltrombopag olamine induces a dose-dependent increase in platelet count. However, platelet levels were observed to gradually return to baseline within two weeks following drug discontinuation^[17]. This finding aligns with the documented risk of bleeding upon cessation of the medication as indicated in the prescribing information. Clinical trials indicate a potential correlation between the duration of eltrombopag olamine administration and the incidence of thrombosis. Specifically, the incidence of thrombosis increased from 2% to 6.3% over a one-year period ^[18]. In this study, cases of ADEs related to thrombosis constituted 5.7% of the total ADE cases, aligning with findings reported in previous literature. Currently, the clinical application of eltrombopag olamine is predominantly long-term; but the risk of thrombosis is still an unavoidable problem. It is recommended that clinicians closely monitor patients' plasma prothrombin time, activated partial thromboplastin time, and thrombin time during treatment, particularly for those with a history of stroke. Regular assessment of coagulation function is advised.

This study identified 73 potential ADEs, representing 32.02% of the total, which were not documented in the current drug instructions available. These ADEs predominantly involved the SOCs of benign, malignant, and unspecified tumors (including cystic and polypoid formations), gastrointestinal disorders, and metabolic nutritional diseases. ADE is mainly divided into blood tumor and solid tumor under benign, malignant and unknown tumors (including cystic and polypoid). Clinical trials involving children with immune thrombocytopenia (ITP) (n = 92) have demonstrated no significant differences in safety between the placebo group and the eltrombopag olamine group, with no occurrences of malignant tumors or hematological malignancies in the experimental cohort^[13]. Additionally, in vitro studies have shown that co-culturing eltrombopag olamine with breast, lung, or ovarian tumor cells does not result in the proliferation of malignant cells^[20]. However, our results show that the number of cases of "myelofibrosis" (a is 76, ROR is 55.74, and the lower limit of 95% CI is 44.24) and the signal intensity is higher. According to the literature, among the patients receiving allogeneic hematopoietic stem cell transplantation, 12/22 patients (54.5%) were detected in biopsy after taking eltrombopag olamine 42days (3-170 ). At the same time, "metastatic ovarian cancer" (a is 3, ROR is 7.183, and the lower limit of 95% CI is 2.308) and "leiomyoma" (a is 3, ROR is 10.855, and the lower limit of 95% CI is 3.481) have not been reported in the manual or previous literature, but there are few reported cases, and their correlation with etoposethan olamine needs further study.

Gastrointestinal diseases encompass eight types of PT signals, among which ADEs not documented in the manual include ascites, oral mucosal blistering, intestinal ischemia, and oral mucosal exfoliation. According to the literature, there is a lack of related research and case reports on the aforementioned ADEs induced by etoposethan olamine, highlighting the need for increased clinical vigilance. Metabolic and nutritional diseases are associated with three types of PT signals, with ADEs not specified in the manual including iron deficiency, iron overload, and emaciation.Etoposethan olamine, functioning as an iron-chelating agent, sequesters cellular iron, a process particularly pertinent in pediatric patients with ITP. Iron deficiency induced by this chelation can detrimentally affect myelination, dopamine signal transduction, and dendritic maturation in neurons, ultimately impairing cognitive functions such as learning and memory^[21]. Consequently, it is imperative to monitor and augment iron supplementation in patients undergoing treatment, with particular emphasis on pediatric cases. Additionally, it is noted in the prescribing information that etoposethan olamine may lead to a reduction in appetite.We hypothesize that this phenomenon may be the direct cause of ADE signal loss; however, further investigation is required to determine whether etoposethan olamine influences glucose and lipid metabolism levels in patients.

In conclusion, it is imperative to remain vigilant regarding the incidence of common ADEs, such as bleeding and thrombosis, and to prioritize the monitoring of ADEs in the context of benign, malignant, and idiopathic tumors, as well as within the immune system, auditory system, and labyrinthine structures, which are often underrepresented or infrequently discussed in standard medical guidelines. Additionally, particular attention should be given to the impact of etoposethan olamine on ADEs in patients undergoing allogeneic hematopoietic stem cell transplantation. Furthermore, this study has certain limitations. The FAERS database relies on spontaneous reporting, with the majority of reports submitted by consumers, which introduces the potential for both misreporting and underreporting. In this study, the ROR method and the PRR method were employed to analyze data at the SOC and SMQ levels. However, these methods only establish a statistical association between etoposethan olamine and ADEs; determining a specific causal relationship necessitates further clinical investigation.

Funding No funding was received.

Availability of Data and Material Data are available on the FAERS database.

Competing Interests The authors declare that they have no competing interests.

Ethics Approval and Consent to Participate Not applicable.

Patient Consent for Publication Not applicable.

Authors' Contributions YB and WK conceived the study and performed the data analysis. LS drafted the manuscript. YB and XPP revised the manuscript. All authors have read and approved the fnal manuscript.

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Bastian TW, Duck KA, Michalopoulos GC, et al. Eltrombopag, a thrombopoietin mimetic, crosses the blood-brain barrier and impairs iron-dependent hippocampal neuron dendrite development. J Thromb Haemost. 2017;15(3):565-574.

No competing interests reported.

Postmarketing safety of eltrombopag olamine : an analysis of the FDA Adverse Event Reporting System (FAERS)

Status:

Version 1

Abstract

1. Introduction

2. Methods

3. Results

4. Discussion

5. Conclusion

Declarations

References

Additional Declarations

Status:

Version 1