Osilodrostat Safety Profile: Findings from Real-World Data in the FAERS Database

Abstract

Background/Objectives: Cushing's syndrome (CS), including Cushing's disease (CD)-the most common type-has a substantial negative impact on morbidity, mortality, and patients' quality of life. Medical management of CS is essential for controlling hypercortisolism as part of preoperative preparation for definitive surgical treatment and for managing residual or relapsed hypercortisolism post-surgery. Osilodrostat, a dual inhibitor of glucocorticoid and mineralocorticoid biosynthetic pathways, has been approved for the medical treatment of CS since early 2020. However, real-world data on its adverse effects remain limited. We mined the FAERS database and analyzed the reports associated with osilodrostat up to 1 October 2024. Methods: Descriptive and disproportionality methods based on Relative Odds Ratio (ROR), Chi-square (χ²), and Proportional Reporting Ratio (PRR), were used to discern potential safety signals and assess the significance of osilodrostat-associated adverse events. Results: This study identified 782 reports in which osilodrostat was the primary suspected drug, containing 593 preferred terms (PTs) and 2481 occurrences. The most frequently registered events belonged to the following SOCs: "General disorders and administration site conditions" (n = 457, 18.4%), "Injury, poisoning and procedural complications" (n = 311, 12.5%), "Gastrointestinal disorders" (n = 278, 11.2%), "Investigations" (n = 260, 10.5%), and "Nervous system disorders" (n = 184, 7.4%). Among PTs, off-label use was the most commonly reported, aligning with the fact that the vast majority of cases originated from the U.S. (84%), where osilodrostat is officially approved only for the treatment of CD. Disproportionality analysis confirmed previously known and new potential adverse drug reactions associated with osilodrostat treatment, including reports of cardiac flutter (n: 4; PRR: 19.42; χ²: 49.57), ventricular extrasystoles (n: 4; PRR: 11.85; χ²: 29.62), muscular weakness (n: 8; PRR: 2.25; χ²: 4.38), rib fracture (n: 4; PRR: 6.66; χ²: 13.99), spinal fracture (n: 3; PRR: 4.66; χ²: 5.35), sepsis (n: 9; PRR: 2.63; χ²: 7.56), fungal infections (n: 4; PRR: 3.67; χ²: 5.33), and COVID-19 (n: 32; PRR: 5.07; χ²: 101.16). Conclusions: This study highlights new risks and offers valuable insights into osilodrostat use; however, further research and validation are necessary, particularly for adverse reactions not yet explicitly documented in the summary of product characteristics.

Keywords: FAERS database; adverse effect; disproportionality analysis; osilodrostat; pharmacovigilance.

Figure 1

Flow chart of data selection for osilodrostat in the FAERS database up to 1 October 2024. ADR—adverse drug reaction; PRR—proportional reporting ratio; PT—preferred term. Data excluded are indicated in red frames.

Figure 2

Distribution of cases by role in ADR occurrence.

Figure 3

Distribution of cases by country of origin. UNK—unknown country.

Figure 4

Distribution of cases by age. NS—not specified.

Figure 5

Distribution of cases by gender. F—female; M—male; NS—not specified.

Figure 6

Distribution of cases with an unfavorable outcome.

Figure 7

The most frequent 30 PTs and the reporting rate. PT—preferred term, %—reporting rate (R).

Figure 8

Distribution of PTs by SOC.

Figure 9

Graphical representation of the strength of probable ADRs related to osilodrostat. The square root of the χ² value is plotted on the Y-axis, and Log₂ROR is plotted on the X-axis. The size of each bubble corresponds to the number of reports for each PT. Each bubble represents a probable ADR, with higher and more distant bubbles indicating stronger relations for osilodrostat use. The red color represents PTs from ‘Endocrine Disorders’, green represents PTs from ‘Injury, Poisoning, and Procedural Complications’ SOC, dark blue represents PTs from ‘Investigations’ SOC, and light blue represents all other PTs.

Figure 10

Reporting odds ratio for probable ADRs. (a)—“Investigations” and “Endocrine disorders”; (b)—“Cardiac disorders”, “Vascular disorders”, “Gastrointestinal disorders”, “General disorders and administration site conditions” and “Metabolism and nutrition disorders”; (c)—“Musculoskeletal and connective tissue disorders”, “Neoplasms benign, malignant and unspecified (incl cysts and polyps)”, “Nervous system disorders”, “Psychiatric disorders”, “Renal and urinary disorders”, “Skin and subcutaneous tissue disorders”, “Surgical and medical procedures”, “Eye disorders” and “Infections and infestations”, “Injury, poisoning and procedural complications”. CD—Cardiac disorders; ED—Eye disorders; PD—Psychiatric disorders; RD—Renal and urinary disorders; SMP—Surgical and medical procedures; VD—Vascular disorders.

Figure 10

Reporting odds ratio for probable ADRs. (a)—“Investigations” and “Endocrine disorders”; (b)—“Cardiac disorders”, “Vascular disorders”, “Gastrointestinal disorders”, “General disorders and administration site conditions” and “Metabolism and nutrition disorders”; (c)—“Musculoskeletal and connective tissue disorders”, “Neoplasms benign, malignant and unspecified (incl cysts and polyps)”, “Nervous system disorders”, “Psychiatric disorders”, “Renal and urinary disorders”, “Skin and subcutaneous tissue disorders”, “Surgical and medical procedures”, “Eye disorders” and “Infections and infestations”, “Injury, poisoning and procedural complications”. CD—Cardiac disorders; ED—Eye disorders; PD—Psychiatric disorders; RD—Renal and urinary disorders; SMP—Surgical and medical procedures; VD—Vascular disorders.