(SLC-045) Mapping the Overall Safety Profile of Levothyroxine-Related Adverse Events: a Disproportionality Analysis on Individual Case Safety Reports Collected by the FAERS

Background: Levothyroxine is widely prescribed for hypothyroidism and thyroid cancer, but concerns about adverse effects, particularly at high doses, persist. Real-world safety data remain limited, warranting further evaluation using FAERS.

Objectives: To assess levothyroxine’s safety profile using FAERS individual case safety reports (ICSRs) via active disproportionality analysis (ADA). The primary objective was to identify and characterize adverse events (AEs). Secondary objectives included detecting dose-specific signals and analyzing age- and gender-related patterns

Methods: Design and Setting: This pharmacovigilance study analyzed FAERS ICSRs (2004–2023) via OpenFDA, where levothyroxine was the primary suspect. Reports were coded using MedDRA (v27.1).
Exposures: (1) Levothyroxine vs. other drugs, (2) High-dose (>100 μg) vs. low-dose (≤100 μg) levothyroxine.
Main Outcome Measures: Levothyroxine-associated AEs identified using MedDRA-v27.1 preferred terms.
Statistical Analysis: Disproportionality analysis was performed using Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Item Gamma Poisson Shrinker (MGPS). Signals required confirmation by all four criteria. Dose-dependent signals were identified using ROR, PRR, and IC025.

Results: Analysis of 45,877 FAERS reports revealed 201,473 AEs linked to levothyroxine. A total of 291 safety signals were identified, including 22 labeled (e.g., alopecia [ROR: 10.25], palpitations [ROR: 13.29], irritability [ROR: 13.49]) and 269 unexpected AEs (e.g., social avoidant behavior [ROR: 48.49], polyglandular autoimmune syndrome type II [ROR: 118.76]).
High-dose levothyroxine (>100 μg) was associated with higher risks of vertigo (ROR: 20.13), celiac disease, and fatigue, supporting a dose-response relationship. AEs were more common in females (67%), with a median age of 52 years (IQR: 41–65). Fatigue, headache, and weight increase were the most frequently reported AEs, with a median onset of 56–143 days.

Conclusions: This study provides a comprehensive safety profile of levothyroxine, identifying both known and unexpected AEs, including those with significant dose-dependent risks. These findings highlight the need for further research to validate signals and elucidate underlying mechanisms.