Signal Mining and Analysis of Adverse Events of Isotretinoin: 20-year real-world pharmacovigilance analysis based on the FAERS database
1Department of Pharmacy, the First People’s Hospital of Yibin City, Sichuan Province, Yibin 644000, China
2School of Pharmacy, Southwest Medical University, Sichuan Province, Luzhou 646000, China
3Personalized Drug Therapy Key Laboratory of Sichuan Province, Department of Pharmacy, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, Affiliated Hospital of University of Electronic Science and Technology of China, Chengdu 610072, China
*Correspondence: Corresponding Author: Yuan Bian, bianyuan567@126.comAbstract
Objective
To identify post-marketing adverse event (AE) signals associated with isotretinoin using real-world data from the U.S. Food and Drug Administration (FDA) AE Reporting System (FAERS), aiming to provide references for clinical safety and further research.
Methods
AE reports from the first quarter of 2004 to the third quarter of 2024 were extracted from the FAERS database. Four signal detection methods were employed: the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Medicines and Healthcare products Regulatory Agency (MHRA) comprehensive criteria, Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS).
Results
A total of 142,160 AE reports involving isotretinoin were collected, corresponding to 50,519 patients. The four methods identified 469 common AE signals. The top five AEs ranked by descending ROR values were: inflammatory bowel disease (ROR=579.14; 95% CI: 554.95-604.39), gastrointestinal injury (ROR=412.80; 95% CI: 381.18-447.04), fulminant acne (ROR=321.42; 95% CI: 236.39-437.04), ulcerative proctitis (ROR=241.56; 95% CI: 201.70-289.30), and premature epiphyseal closure (ROR=221.22; 95% CI: 172.47-283.74). Among the top 30 AE signals, several conditions, including nasal vestibulitis, anal papilla hypertrophy, neonatal neuroblastoma, diverticular hernia, SAPHO syndrome, somatic delusional disorder, hypersomnia-bulimia syndrome, and hemihypertrophy, were not listed in the drug’s prescribing information. The AE signals involved 25 system organ classes, predominantly psychiatric disorders (75, 15.99%), gastrointestinal disorders (58, 12.37%), and various congenital, familial, and genetic disorders (50, 10.66%). Additionally, strong signals related to pregnancy events were detected, notably unintended pregnancy (ROR=91.39; 95% CI: 86.78-96.26).
Conclusion
AE signals associated with isotretinoin involve a broad spectrum of system organ classes. Comprehensive monitoring during clinical use is essential, particularly concerning psychiatric and gastrointestinal disorders. Given the strong signals regarding teratogenicity and pregnancy-related events, strengthening preventive measures for pregnancy risks in patients is recommended.
Article notes
Competing Interest Statement
The authors have declared no competing interest.
Funding Statement
The author(s) received no specific funding for this work.
1Introduction
Isotretinoin is a first-generation, non-aromatic retinoid drug. It significantly improves acne symptoms by inhibiting sebaceous gland sebum secretion, regulating abnormal keratinization of sebaceous gland ducts in hair follicles, exerting anti-inflammatory effects, and preventing scar formation. In 1982, isotretinoin was approved by the FDA for patients aged 12 years and older with severe refractory nodular acne. Clinically, it is also widely used to treat refractory or persistent moderate-to-severe acne, as well as acne prone to scarring or significant psychological distress [0-Error! Reference source not found.]. In recent years, isotretinoin has been frequently utilized beyond prescribing indications for psoriasis, cutaneous lupus erythematosus, other skin diseases [Error! Reference source not found.,Error! Reference source not found.], ichthyosis and other disorders of cornification [Error! Reference source not found.], and as maintenance therapy for high-risk neuroblastoma in children [7]. Currently, isotretinoin is commercially available in multiple countries worldwide, and safety concerns regarding its use continue to attract attention. Research indicates a high incidence of adverse reactions involving multiple organ systems, including depression, inflammatory bowel disease (IBD), liver dysfunction, and hypertriglyceridemia [Error! Reference source not found.]. However, its association with certain adverse reactions, such as IBD and depression, remains controversial. Therefore, a systematic analysis of large-scale, real-world data is necessary to clarify potential risks. In addition, isotretinoin is teratogenic. Prescribing information from multiple countries strongly warns that women of childbearing age must strictly use contraception while taking isotretinoin. However, the effectiveness of these recommendations requires verification through additional real-world studies. This study will also focus on pregnancy-related events occurring during isotretinoin treatment.
The FAERS system in the United States collects large-scale real-world AE reports through a public voluntary reporting format, characterized by a large sample size and strong timeliness [Error! Reference source not found.]. Systematic analysis of the FAERS database enables the identification of potential drug risks, making it a critical tool for drug safety monitoring and pharmacovigilance.
This study conducts signal mining of isotretinoin-related AEs using real-world data from the FAERS database. Consequently, the safety profile of isotretinoin in actual clinical practice can be comprehensively evaluated. The findings of this study aim to provide a scientific basis for clinical drug management, enhance patient medication safety, and assist drug regulatory agencies in identifying, warning, and formulating policies related to potential drug risks.
2Data and Methods
2.1Data sources
This study extracted 83 quarters of data from the FAERS database in the United States, spanning the first quarter of 2004 to the third quarter of 2024. All the data can be accessed at https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html. Definitions for FAERS database fields can be found on the FDA official website. The dataset comprised seven subsets of data, including demographic and administrative information (DEMO), drug/biological information (DRUG), adverse drug reaction information (REAC), patient outcomes information (OUTC), report source information (RPSR), drug therapy start and end dates (THER), and indications for use or diagnosis (INDI).
2.2Data cleaning and standardization
Duplicate, revoked, or deleted reports in the FAERS database required cleaning. First, duplicate reports were removed using the FDA-recommended method. The PRIMARYID, CASEID, and FDA_DT fields from the DEMO table were selected and sorted by CASEID, FDA_DT, and PRIMARYID. For reports with identical CASEID, the record with the latest FDA_DT was retained. For records with identical CASEID and FDA_DT, the report with the highest PRIMARYID was retained. Second, reports identified in the list of deleted reports were removed based on CASEID. Finally, AEs were classified and standardized using preferred terms (PT) and system-organ classification (SOC) from the MedDRA (version 27.1). A comprehensive flowchart outlining the study design is presented in Fig 1.
2.3Statistical analysis
Data processing and statistical analysis were conducted using Microsoft Excel and SAS 9.4 software. Descriptive analysis was applied to characterize all AE reports related to isotretinoin. Currently, multiple methods are commonly employed to jointly mine AE signals. This study used four signal detection methods to enhance research credibility: ROR, PRR based on the MHRA comprehensive criteria, BCPNN, and MGPS methods [Error! Reference source not found.-Error! Reference source not found.]. Data were classified and statistically analyzed using a four-grid table (see Table 1). Signals identified as positive by all four detection methods were considered risk signals associated with isotretinoin. The comprehensive criteria for signal determination were: a ≥ 3, lower limit of the ROR 95% confidence interval > 1, PRR ≥ 2 and χ 2 ≥ 4, IC-2SD > 0, and EBGM05 > 2. Specific calculation formulas and signal criteria are presented in Table 2.
3Results
3.1Basic information and demographic characteristics of AE reports
The number of background patients included in this study was 18,278,243 (with 54,336,884 AEs), while the number of patients administered isotretinoin was 50,519 (with 142,160 AEs). According to statistics, the number of AE reports related to isotretinoin gradually increased each year. Regarding patient gender, females accounted for 55.44%, males for 33.21%, and unknown gender for 11.35%. Patients were predominantly young, with 34.07% aged between 18 and 44 years, and 19.15% younger than 18 years. The United States was the primary reporting country, accounting for 80.14% of reports. Physicians (33.47%) and consumers (29.52%) were the main reporters. Specific details are provided in Table 3.
3.2Signal intensity of AEs related to isotretinoin
This study identified 469 positive AE signals related to isotretinoin through the joint application of four methods. The AE signals detected by each method were generally consistent, as shown in Table 4. Furthermore, these results were mostly consistent with AE occurrences documented in isotretinoin prescribing information, confirming the credibility of the analytical method. Ranked in descending order by ROR values, the top ten AEs were IBD, gastrointestinal injury, acne fulminans, ulcerative proctitis, premature epiphyseal closure, nasal vestibulitis, induced complete abortion, selective abortion, xerosis, and epiphyseal injury. Comparing these results with the prescribing information revealed several AEs not previously documented, including nasal vestibulitis, hypertrophic anal papilla, neonatal neuroblastoma, diverticular hernia, SAPHO syndrome, somatic delusional disorder, hypersomnia-bulimia syndrome, and hemihypertrophy.
3.4Onset Time of AEs
After excluding reports with inaccurate, missing, or unknown onset times, a total of 12,575 AEs associated with isotretinoin provided valid onset-time data. The results indicated a median AE onset time of 72 days (interquartile range [IQR]: 26–171 days), with more than half of the cases occurring within the first three months of treatment (0–30 days: n = 3,742, 29.76%; 31–60 days: n = 1,872, 14.89%; 61–90 days: n = 1,436, 11.42%). Moreover, the incidence of AEs after six months of treatment was considerable, showing an increasing trend and accounting for 23.98% of the total cases (181–360 days: n = 1,107, 8.80%; >360 days: n = 1,909, 15.18%). The timeline of these events is illustrated in Fig 2, and the cumulative incidence curve of AEs is presented in Fig 3.
4Discussion
4.3Onset time of isotretinoin-associated adverse events
The findings of this study indicated that the median onset time of adverse events in patients treated with isotretinoin was 72 days, with the majority of cases occurring within the first three months after initiating therapy. Furthermore, the incidence of AEs exhibited an upward trend after six months of treatment. Thus, in clinical practice, careful monitoring for AEs is particularly important within the initial three months of treatment as well as after six months of continued isotretinoin use to ensure patient safety.
4.4AE signals of key concern
4.4.2Isotretinoin and IBD
This study found that IBD ranked first in signal intensity and second in reported events, demonstrating exceptionally strong signal strength. Some studies indicate isotretinoin may induce IBD by disrupting intestinal barrier function and activating the immune system. However, large-scale population studies over the past decade, recent meta-analyses, and clinical guidelines suggest that IBD onset strongly correlates with genetic, environmental, and immune factors. These confounders commonly exist in study populations, and thus a direct causal relationship between isotretinoin and IBD remains unproven [Error! Reference source not found.,Error! Reference source not found.-Error! Reference source not found.].
Given these conclusions, the current study further analyzed possible reasons for the strong correlation between isotretinoin and IBD. After 2009, multiple lawsuits against isotretinoin manufacturers occurred in the United States, significantly increasing reported IBD cases between 2009 and 2012. Prior studies indicate that a large proportion of FAERS reports linking isotretinoin to IBD were submitted by law firms, suggesting potential legally driven overreporting [Error! Reference source not found.,Error! Reference source not found.].
Further analysis of the raw data showed that 5,278 IBD reports existed, among which 4,483 (84.94%) were submitted by lawyers. Analyzing reporting years revealed that 4,526 cases (85.75%) were reported between 2009 and 2014. Since 2018, fewer than 10 reports per year have been submitted, again highlighting potential legally driven overreporting after 2009. Considering these factors, the strong positive IBD signal found in this study likely reflects significant reporting bias. Therefore, larger prospective studies are needed to further investigate the relationship between isotretinoin and IBD. Nevertheless, close monitoring of gastrointestinal symptoms during isotretinoin use remains advisable, particularly for patients with a family history of IBD or those diagnosed with IBD.
4.4.3Teratogenicity of isotretinoin
Isotretinoin can cross the placental barrier and is classified as Grade X by the FDA regarding pregnancy safety. Clinical studies have shown that oral administration of isotretinoin increases the risk of severe congenital malformations, spontaneous abortion, and premature birth [Error! Reference source not found.]. This study found isotretinoin ranked third among positive signals involving congenital, familial, and genetic disorders, mainly affecting the ears and labyrinth, central nervous system, cardiovascular system, musculoskeletal system, and eyes. This finding aligns with the drug prescribing information and existing literature [Error! Reference source not found.,Error! Reference source not found.]. The top ten identified congenital abnormalities included congenital middle ear abnormalities, anorectal malformations, congenital cerebellar hypoplasia, congenital optic nerve abnormalities, hemihypertrophy, congenital inner ear abnormalities, cerebellar dysplasia, anophthalmia, congenital ear malformations, and follicular keratosis. Special attention should be given to hemihypertrophy and follicular keratosis, which have strong positive signals but are not mentioned in isotretinoin prescribing information. Current studies suggest potential associations between isotretinoin exposure and partial developmental asymmetry, unilateral abnormal growth, skin dysplasia, and keratinization disorders [Error! Reference source not found.,Error! Reference source not found.], though definitive correlations remain unconfirmed. Further research should explore these relationships.
4.4.4Isotretinoin and pregnancy events
This study reported 6,453 AE occurrences related to pregnancy, puerperium, and perinatal conditions, with 4,641 (71.92%) specifically categorized as pregnancy events. Among these, unexpected pregnancy displayed strong positive signals, ranking within the top 30 AE signals. These findings highlight the necessity of enhanced management of pregnancy events in clinical practice. Isotretinoin carries a high risk of severe birth defects and is contraindicated in pregnant women or those who may soon become pregnant. According to prescribing information in some countries, such as China, women of childbearing age or their spouses must use effective contraception within three months before isotretinoin use, during treatment, and for three months after cessation. The US FDA guidelines require contraception for at least one month before starting medication, during treatment, and for three months after discontinuation. Pregnancy prevention programs, such as the iPLEDGE program in the United States, have been implemented internationally to reduce isotretinoin-associated fetal malformation risks by ensuring strict contraception before and after administration [Error! Reference source not found.,Error! Reference source not found.].
Despite these programs, 3.3%–6.5% of isotretinoin users still experience pregnancy during treatment [Error! Reference source not found.]. Key reasons include insufficient patient compliance with contraception, inadequate education regarding pregnancy prevention, and improper contraceptive method selection. Research suggests some patients fail to fully understand isotretinoin’s severe teratogenic risks before treatment. Combined with poor contraceptive compliance, this leads to a high incidence of unintended pregnancies [Error! Reference source not found.].
Based on these findings, clinical doctors or pharmacists must remind patients to strictly use contraception during and after isotretinoin treatment. Patients should prioritize highly effective contraceptive methods or multiple contraceptive strategies. Pregnancy monitoring should be strengthened, and enhanced patient education is essential for improving compliance. Government regulatory agencies should further strengthen and improve pregnancy prevention measures to ensure the safe use of isotretinoin.
5Research Innovations and Limitations
5.1Research Innovations
5.1.1Methodological Innovation
We pioneered the systematic integration of four internationally recognized pharmacovigilance algorithms (ROR, PRR, BCPNN, MGPS). This integrated approach was applied to a comprehensive analysis of 142,160 adverse event reports associated with isotretinoin spanning two decades (2004– 2024) from the FAERS database. This significantly enhanced the robustness of signal detection and the identification capability for rare events.
5.1.2Expansion of the Risk Profile
We established the most comprehensive adverse event profile for isotretinoin to date, identifying 469 consolidated safety signals. Notably, 8 previously unlisted signals (including nasal vestibulitis, anal papilla hypertrophy, and neonatal neuroblastoma) offer novel evidence for updating global safety information in prescribing documents.
5.1.3Novel Risk Management Findings
Unintended pregnancy (ROR=91.39) emerged as the strongest pregnancy-related signal. This finding provides critical empirical evidence for optimizing global Pregnancy Prevention Programs (e.g., iPLEDGE) and highlights potential vulnerabilities in current risk management protocols.
5.2Research Limitations
Although this study analyzed a large amount of real-world data, certain limitations remain. (1) The data analyzed were primarily reported from European and American countries, potentially influenced by racial and regional differences. (2) Due to the spontaneous reporting nature of the database, some information might be misreported or underreported, potentially affecting research results. (3) Detected AE signals indicate only a statistical correlation between the drug and AE, and their clinical significance requires further verification through clinical trials.
6Conclusions
In summary, this study utilized the FAERS database in the United States and employed SAS 9.4 software with four detection methods to identify AE signals associated with isotretinoin in the real world. Findings indicated that AEs were primarily concentrated in psychiatric and gastrointestinal disorders, aligning with the prescribing information for isotretinoin. In clinical practice, monitoring and follow-up should be enhanced. The study also identified AE signals not documented in the prescribing information, including nasal vestibulitis, hypertrophic anal papilla, neonatal neuroblastoma, diverticular hernia, SAPHO syndrome, somatic delusional disorder, hypersomnia-bulimia syndrome, and hemihypertrophy, which require special attention. Additionally, this study detected extremely high-risk signals related to severe birth defects and pregnancy events. Therefore, further efforts are necessary to strengthen medication education for patients and preventive management measures concerning pregnancy events to ensure medication safety. Due to inherent difficulties in quantitative analysis based on real-world data, these findings still require verification through large-scale prospective studies.
Data Availability
All the source data can be accessed at https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html. Definitions for FAERS database fields can be found on the FDA official website. All relevant data are within the manuscript and its Supporting Information files.
https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html
Funding
This research received no external funding.
Institutional Review Board Statement
Ethical approval was not required as the study involved analysis of publicly available anonymized data that posed no risk to participants. According to local regulations and institutional requirements, this human subjects research did not require ethical approval. In compliance with national regulations and institutional policies, written informed consent from participants or their legal guardians/next of kin was not required for this study.
Informed Consent Statement
Informed consent was not required given the exclusive use of anonymized, non-identifiable data.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Data Availability
All raw data required to replicate the study results are included in the manuscript and Supporting Information files. The data used in the analysis are publicly available via the FDA FAERS database, as stated in the Methods section: https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.
Conflicts of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.