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Original Article
Comprehensive Analysis of Mitotane-Related Adverse Events Using the Food and Drug Administration Adverse Event Reporting System
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Xing Wang, MD, Jun Li, MD, Yunfeng Zhang, PhD, Ruizhen Huang, MD, Penglin Zhang, MM, Honglin Hu, MD *
Department of Urology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
ARTICLE INFO
Article history: Received 19 October 2024 Received in revised form 6 November 2024 Accepted 14 November 2024 Available online 19 November 2024
Key words: adrenocortical carcinoma disproportionality analysis FAERS mitotane rare tumors
ABSTRACT
Objective: Mitotane is currently the only product approved by the Food and Drug Administration for the treatment of adrenocortical cancer. However, there is a lack of comprehensive studies on the adverse events of mitotane.
Methods: Adverse event reports for mitotane in the Food and Drug Administration Adverse Event Reporting System database since 2004 were collected and analyzed to identify mitotane as the primary suspect drug. Reporting ratios, multi-item y Poisson constrictors, proportional reporting ratios, and Bayesian confidence propagation neural networks were used to analyze the dis- proportionality of mitotane-related adverse events.
Results: A total of 21 433 114 adverse event reports were retrieved from the Food and Drug Administration Adverse Event Reporting System database, with 772 cases identified where mitotane was the primary suspected drug. Positive signals were observed for adverse reactions listed on the drug label, such as nausea, diarrhea, vomiting, dizziness, loss of appetite, and adrenal insufficiency. Additionally, potential adverse reactions not specified on the label were detected, including fatigue, malignant tumor progression, ovarian cysts, chills, amnesia, and Q-T interval prolongation on the electrocardiogram. These findings highlight the critical need for vigilant monitoring of adverse events, particularly during the first few months of treatment.
Conclusion: This study provides preliminary safety data on the practical application of mitotane, confirming some known adverse reactions and revealing other potential risks. These findings pro- vide critical safety information for clinicians prescribing mitotane for the treatment of adrenocortical cancer.
@ 2024 AACE. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
Introduction
Adrenocortical carcinoma (ACC) is a rare but highly aggressive endocrine cancer, affecting approximately 1 to 2 individuals per million each year, predominantly middle-aged women. Often diagnosed at advanced stages, ACC has a poor 5-year survival rate ranging from 16% to 47%. The disease progresses rapidly, and about 60% of cases involve hormone overproduction, leading to complex symptoms such as Cushing’s syndrome, which further complicates
treatment.2 While surgery is the primary treatment for localised ACC, recurrence rates remain high, particularly for more giant tu- mors.3 Given its rarity and challenging nature, options for effective adjuvant and palliative treatments are limited. The European Medicines Agency and the U.S. Food and Drug Administration (FDA) approve mitotane as the only treatment for advanced ACC. Mito- tane is difficult to administer. Often viewed through the prism of cytotoxic drugs, it also interferes with hormone production, mak- ing it a valuable asset in managing functional ACC.4 When used cautiously and thoughtfully, especially in patients with hormonal overload, mitotane is an important part of the ACC therapeutic armamentarium.5
Mitotane is an analogue of the insecticide dichlorodiphenyltri- chloroethane and is used to treat ACC. Its chemical structure is shown in Supplementary Fig. 1. Mitotane may alter the peripheral metabolism of steroids and inhibit adrenal steroidogenesis through
Abbreviations: ACC, adrenocortical carcinoma; FAERS, Food and Drug Adminis- tration Adverse Event Reporting System; FDA, Food and Drug Administration.
* Address correspondence to Dr Honglin Hu, Department of Urology, the Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang 330006, Jiangxi Province, PR China.
E-mail address: honglinhu@126.com (H. Hu).
metabolite inhibition of enzymes in the steroid synthesis pathway, including cholesterol side-chain cleavage enzymes, CYP11A1 and CYP11B1 metabolites. Mitotane is the only adrenergic solubilising agent available for the treatment of ACC, and the mechanism of action is currently unknown.7 As a very rare disease with hetero- geneous disease behaviour, there are fewer reports on the thera- peutic efficacy and adverse events of mitotane in the treatment of ACC. As of today, there is still a lack of comprehensive analyses of the safety of mitotane in the real world, and most of the available safety data show some limitations. Most data come from clinical trials and retrospective analyses of small samples.8,9 Accordingly, mining potential adverse events associated with the use of mito- tane is critical to its safety assessment.
The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) is a publicly accessible database of adverse event reports containing a vast amount of data submitted voluntarily by consumers, physicians, and pharmacists.10,11 It plays a significant role in ensuring the safe use of medications. In recent years, the FAERS database has uncovered numerous adverse drug reaction timings, such as adverse reactions associated with rivaroxaban and adverse events in patients with advanced urothelial carcinoma treated with erdafitinib.12 This study evaluated the real-world safety of mitotane through disproportionality analysis of data from the FAERS database. These findings may guide clinicians in the safe use of this medication.
Methods
Data Sources, Management, and Study Design
The FAERS database is a publicly accessible resource where reports are primarily submitted by consumers, physicians, and pharmacists worldwide. For this study, data were sourced from the FAERS database, focusing on cases where mitotane was identified as the primary suspect drug, covering the period from the first quarter of 2004 to the third quarter of 2024. The data were processed following standard procedures in line with FDA guidelines, which included the use of standardized adverse
Highlights
. Comprehensive assessment of mitotane-related adverse events using the FAERS database
· Known adverse events confirmed, including nausea, diarrhea, and adrenal insufficiency
· New potential adverse events identified, such as fatigue, ovarian cysts, and Q-T interval prolongation
. Proactive monitoring is critical, especially in the early months of treatment
Clinical Relevance
This study offers crucial safety insights for clinicians prescribing mitotane for adrenocortical cancer, underscoring the impor- tance of early monitoring and personalized risk management to enhance patient care.
event terminology and prioritization rules. When multiple re- ports shared the same case identifier (CASEID), only the report with the most recent FDA receipt date (FDA_DT) was kept. If both CASEID and FDA_DT were identical, the report with the highest PRIMARYID (the unique report identifier) was selected. Adverse event terminology was standardized using the MedDRA dictionary. A detailed flow chart of the study methodology is presented in Fig. 1. This study was exempt from Institutional Review Board approval because of the use of unidentified data.
Statistical Analysis
Four mismatch analyses were used to detect positive ADR signals: proportional reporting ratio,13 reporting ratio of ratios,14 multi-item Y Poisson Shrinker,15 and Bayesian confidence propagation neural network.16 Adverse events with a positive threshold for at least one
DEMO (n=21433114)
Duplication records (n=3476461)
DRUG (n=65083962)
DEMO removed duplication (n=17956653)
REAC (n=52454964)
Adverse event reporting of mitotane as the PS (n=772)
Adverse event induced by mitotane as the PS (n=2900)
Adverse event reporting of mitotane as the PS (n=772)
Clinical characteristics
Signal Detection
Stratification analysis
Time-to-onset analysis
| Characteristics | Case numbers | Case proportion (%) |
|---|---|---|
| Number of events | 772 | |
| Gender | ||
| Male | 241 | 31.2% |
| Female | 490 | 63.5% |
| Miss | 41 | 5.3% |
| Age | ||
| < 18 | 50 | 6.5% |
| 18-65 | 442 | 57.3% |
| 65-85 | 143 | 18.5% |
| Miss | 137 | 17.7% |
| Top 5 reported countries | ||
| United States | 415 | 53% |
| France | 165 | 21.4% |
| Germany | 20 | 2.6% |
| Netherlands | 11 | 1.4% |
| Italy | 10 | 1.3% |
| Reporter | ||
| Consumer | 482 | 62.4% |
| Medical doctor | 116 | 15% |
| Other | 111 | 14.4% |
| Pharmacists | 43 | 5.6% |
| Health care professional | 18 | 2.3% |
| Top 5 reporting year | ||
| 2024 | 131 | 17% |
| 2023 | 108 | 14% |
| 2022 | 87 | 11% |
| 2021 | 57 | 7% |
| 2018 | 50 | 6% |
of the above 4 methods were considered to be positive signals for adverse reactions 2 x 2. The list of columns is detailed in Supple- mentary Table 1. Formulas and thresholds for disproportionality analyses are described in Supplementary Table 2. The interval be- tween the occurrence of an adverse event (as reported in the DEMO file) and the start of mitotane treatment (as documented in the THER file) defined the onset time of mitotane-associated adverse events. The Weibull distribution was used to model the change in the inci- dence of adverse events over time. All analysis was performed using R software version 4.3.2.
Results
Fundamental Information Concerning Adverse Event Reports
From the first quarter of 2004 to the third quarter of 2024, a total of 772 reports of adverse events (out of a total of 2900 adverse events) were identified in FAERS, with mitotane as the main causative factor. Of these, 31.2% were male patients, and 63.5% were female patients. The majority of cases involved individuals aged 18- 65, making up 57.3% of the reports. Most submissions were made voluntarily by consumers, representing 62.4% of the total, followed by medical doctors at 15%. Of these, 43.8% were from the United States, followed by France and Germany with 21.4% and 2.6%, respectively. Please refer to Table 1 for detailed data.
Distribution of Adverse Events at the System Organ Class Level
Out of the 27 system organ classes, 25 were found to have adverse events associated with mitotane. As indicated in Table 2,
| System Organ Class (SOC) | Case numbers | ROR (95% CI) | PRR (c2) | EBGM (EBGM05) | IC (IC025) |
|---|---|---|---|---|---|
| Eye disordersª | 32 | 0.55 (0.39-0.77) | 0.55 | 0.55 | -0.86 (-2.53) |
| Investigationsª | 230 | 1.3 (1.13-1.48) | 1.27 | 1.27 | 0.35 (-1.32) |
| General disorders and administration site conditionsª | 464 | 0.9 (0.81-0.99) | 0.92 | 0.92 | -0.13 (-1.79) |
| Metabolism and nutrition disordersª | 143 | 2.35 (1.99-2.78) | 2.29 | 2.28 | 1.19 (-0.47) |
| Psychiatric disordersª | 126 | 0.74 (0.62-0.89) | 0.76 | 0.76 | -0.41 (-2.07) |
| Gastrointestinal disordersª | 501 | 2.23 (2.02-2.45) | 2.01 | 2.01 | 1.01 (-0.66) |
| Injury, poisoning, and procedural complicationsª | 199 | 0.72 (0.62-0.83) | 0.74 | 0.74 | -0.43 (-2.1) |
| Ear and labyrinth disordersª | 20 | 1.59 (1.03-2.48) | 1.59 | 1.59 | 0.67 (-1) |
| Nervous system disordersª | 421 | 1.82 (1.64-2.02) | 1.7 | 1.7 | 0.77 (-0.9) |
| Infections and infestationsª | 77 | 0.49 (0.39-0.61) | 0.5 | 0.5 | -0.99 (-2.66) |
| Product issuesª | 13 | 0.28 (0.16-0.49) | 0.29 | 0.29 | -1.8 (-3.47) |
| Skin and subcutaneous tissue disordersª | 93 | 0.58 (0.47-0.72) | 0.6 | 0.6 | -0.75 (-2.42) |
| Musculoskeletal and connective tissue disordersª | 60 | 0.38 (0.29-0.49) | 0.39 | 0.39 | -1.36 (-3.03) |
| Neoplasms benign, malignant, and unspecified (including cysts and polyps) | 68 | 0.87 (0.68-1.11) | 0.87 | 0.87 | -0.19 (-1.86) |
| Cardiac disordersª | 16 | 0.2 (0.12-0.33) | 0.21 | 0.21 | -2.28 (-3.95) |
| Hepatobiliary disordersª | 46 | 1.74 (1.30-2.33) | 1.73 | 1.73 | 0.79 (-0.88) |
| Reproductive system and breast disordersª | 41 | 1.71 (1.26-2.33) | 1.7 | 1.7 | 0.77 (-0.9) |
| Surgical and medical proceduresª | 19 | 0.48 (0.31-0.76) | 0.49 | 0.49 | -1.04 (-2.71) |
| Vascular disordersª | 42 | 0.66 (0.49-0.90) | 0.67 | 0.67 | -0.59 (-2.25) |
| Endocrine disordersª | 102 | 14.31 (11.75-17.44) | 13.85 | 13.84 | 3.79 (2.12) |
| Renal and urinary disordersª | 25 | 0.46 (0.31-0.68) | 0.46 | 0.46 | -1.11 (-2.77) |
| Blood and lymphatic system disordersª | 84 | 1.72 (1.38-2.14) | 1.7 | 1.7 | 0.76 (-0.9) |
| Respiratory, thoracic and mediastinal disordersª | 52 | 0.36 (0.28-0.48) | 0.37 | 0.37 | -1.42 (-3.09) |
| Pregnancy, puerperium, and perinatal conditions | 7 | 0.55 (0.26-1.17) | 0.56 | 0.56 | -0.85 (-2.51) |
| Social circumstances | 6 | 0.48 (0.21-1.16) | 0.48 | 0.48 | -1.07 (-2.73) |
| Congenital, familial, and genetic disordersª | 2 | 0.22 (0.06-0.90) | 0.22 | 0.22 | -2.15 (-3.82) |
Asterisks (*) denote statistically significant signals in the algorithm.
Abbreviations: AE = adverse event; CI = confidence interval; EBGM = empirical Bayesian geometric mean; EBGM05 = the lower bound of the 95% confidence interval for EBGM; IC = information component; IC025 = the lower bound of the 95% confidence interval for IC; PRR = proportional reporting ratio; ROR = reporting odds ratio. a Statistically significant signals identified through disproportionality analysis.
Number of Adverse Reactions by SOC
Gastrointestinal Disorders
501
General Disorders And Administration Site Conditions
464
Nervous System Disorders
421
Investigations
230
Injury. Poisoning And Procedural Complications
199
SOC
Metabolism And Nutrition Disorders
143
Blood And Lymphatic System Disorders
Psychiatric Disorders
126
Cardiac Disorders
Endocrine Disorders
102
Congenital, Familial And Genetic Disorders
Skin And Subcutaneous Tissue Disorders
93
Ear And Labyrinth Disorders
Eye Disorders
SOC (System Organ Class)
Blood And Lymphatic System Disorders
84
General Disorders And Administration Site Conditions
Infections And Infestations
77
Hepatobiliary Disorders
Neoplasms Benign, Malignant And Unspecified (Ind Cysts And Polyps)
68
Injury, Poisoning And Procedural Complications
Musculoskeletal And Connective Tissue Disorders
60
Investigations
Respiratory, Thoracic And Mediastinal Disorders
52
Metabolism And Nutrition Disorders
Hepatobiliary Disorders
46
Musculoskeletal And Connective Tissue Disorders
Vascular Disorders
42
Nervous System Disorders
Pregnancy. Puerperium And Perinatal Conditions
Reproductive System And Breast Disorders
41
Psychiatric Disorders
Eye Disorders
32
Renal And Urinary Disorders
Renal And Urinary Disorders
25
Reproductive System And Breast Disorders
Ear And Labyrinth Disorders
20
Respiratory. Thoracic And Mediastinal Disorders
Surgical And Medical Procedures
19
Skin And Subcutaneous Tissue Disorders
Social Circumstances
Cardiac Disorders
16
Product Issues
13
Pregnancy, Puerperium And Perinatal Conditions
Social Circumstances
Congenital, Familial And Genetic Disorders
0
100
200
Number of Cases
300
400
500
significant associations were observed across various categories, including gastrointestinal disorders, general disorders and admin- istration site conditions, nervous system disorders, investigations, metabolic and nutritional disorders, psychiatric disorders, and endocrine disorders. The distribution of these adverse events by system organ class is illustrated in Fig. 2.
Distribution of Adverse Events at the Preferred Term Level
The frequency of adverse events associated with mitotane was firstly ranked, and secondly positive signals were assessed. Of the 50 most common adverse reactions, known adverse reactions identified included nausea, diarrhoea, vomiting, dizziness, decreased appetite, and adrenal insufficiency, to name a few. Moreover, several potential adverse reactions not listed on the label were identified, including fatigue, malignant tumour progression, ovarian cysts, chills, memory impairment, and prolonged Q-T in- terval (QT) interval on the electrocardiogram. Detailed information on these findings is provided in Table 3. Additionally, all adverse events that met the criteria for positive signals have been docu- mented in Supplementary Table 3.
Subgroup Analysis
Adverse events associated with mitotane were analyzed in subgroups of gender and age. In the gender subgroup analyses, of the 50 most common adverse events that met the criteria for a positive signal, those occurring only in males included hypo- gonadism, pneumonia, muscular weakness, and dehydration, whereas rash, vertigo, balance disorder, and hypercholesterolaemia were female-specific adverse events. Detailed information on the analyses of the male and female subgroups is presented in Supplementary Tables 4 and 5. In addition, from the age subgroup analyses, with regard to patients under 18 years of age, precocious puberty, decreased weight, adrenal insufficiency, and acute adre- nocortical insufficiency were also common adverse reactions, and none of the reported events were outside the scope of the drug labelling. In patients aged 18-65 years, the 50 most common adverse events showed positive signals, including nausea, fatigue,
diarrhoea, vomiting, and dizziness, among others. With respect to patients over 65 years of age, common adverse events included fatigue, nausea, and decreased appetite, among others. Detailed information on the analysis for each age subgroup is available in Supplementary Tables 6, 7, and 8.
Sensitivity Analysis
Mitotane is commonly used in combination with cisplatin, etoposide, doxorubicin, hydrocortisone, capecitabine, and other drugs in clinical dosing. After excluding cases with concomitant use of other drugs, we identified 554 reports documenting 2190 adverse events. The recurring potential adverse events included nausea, fatigue, diarrhoea, vomiting, off-label use, and dizziness (Supplementary Table 9).
Time of Onset and Weibull Distribution Analysis of Adverse Events
With respect to time of onset, the adverse events associated with mitotane occurred mainly within a few months of treatment. The detailed timing of these events is illustrated in Fig. 3. The cu- mulative incidence curve of adverse events is also depicted in Fig. 4. The Weibull distribution analysis reveals a trend of early failure, with detailed parameters listed in Table 4.
Discussion
This study comprehensively assessed the adverse reactions associated with mitotane since its introduction to the market in 2004. Our results confirmed adverse reactions consistent with mitotane’s drug insert, including gastrointestinal symptoms (eg, nausea, diarrhoea, vomiting), adrenal insufficiency and neurolog- ical symptoms (eg, dizziness, tremors). In addition, our analyses identified a number of new potential adverse events, such as ovarian cysts, malignancy progression and prolonged electrocar- diographic QT intervals, which are not currently listed on the drug label. These findings highlight the importance of continuous pharmacovigilance monitoring of mitotane safety in practice to effectively manage and mitigate potential adverse events.
| PT | Case numbers | ROR (95% CI) | PRR (c2) | EBGM (EBGM05) | IC (IC025) |
|---|---|---|---|---|---|
| Nauseaª | 167 | 4.63 (3.96-5.41) | 4.42 (447.16) | 4.42 (3.87) | 2.14 (0.48) |
| Fatigueª | 153 | 4.3 (3.65-5.05) | 4.12 (366.32) | 4.12 (3.6) | 2.04 (0.38) |
| Diarrhoeaª | 100 | 3.37 (2.76-4.11) | 3.29 (160.84) | 3.29 (2.78) | 1.72 (0.05) |
| Vomitingª | 85 | 3.9 (3.14-4.84) | 3.82 (177.98) | 3.82 (3.19) | 1.93 (0.27) |
| Off label useª | 78 | 2.09 (1.67-2.61) | 2.06 (42.96) | 2.06 (1.7) | 1.04 (-0.63) |
| Dizzinessª | 70 | 2.95 (2.33-3.74) | 2.91 (88.27) | 2.91 (2.38) | 1.54 (-0.13) |
| Astheniaª | 61 | 3.41 (2.65-4.39) | 3.36 (101.68) | 3.36 (2.72) | 1.75 (0.08) |
| Decreased appetiteª | 54 | 5.03 (3.84-6.58) | 4.95 (170.99) | 4.95 (3.95) | 2.31 (0.64) |
| Malignant neoplasm progressionª | 46 | 9.89 (7.39-13.23) | 9.74 (361.38) | 9.74 (7.63) | 3.28 (1.62) |
| Adrenal insufficiencyª | 46 | 90.98 (67.94-121.83) | 89.55 (4008.63) | 89.11 (69.79) | 6.48 (4.81) |
| Weight decreaseda | 42 | 3.15 (2.32-4.27) | 3.11 (60.58) | 3.11 (2.41) | 1.64 (-0.03) |
| Somnolenceª | 31 | 3.21 (2.25-4.57) | 3.18 (46.61) | 3.18 (2.37) | 1.67 (0) |
| Abdominal discomfortª | 25 | 3.17 (2.14-4.7) | 3.15 (36.78) | 3.15 (2.27) | 1.66 (-0.01) |
| Balance disorderª | 23 | 5.43 (3.6-8.18) | 5.39 (82.42) | 5.39 (3.83) | 2.43 (0.76) |
| Drug level above therapeuticª | 21 | 99.97 (65-153.74) | 99.25 (2031.44) | 98.71 (68.86) | 6.63 (4.96) |
| Depressionª | 21 | 1.85 (1.2-2.84) | 1.84 (8.11) | 1.84 (1.29) | 0.88 (-0.79) |
| Memory impairmentª | 20 | 2.99 (1.93-4.65) | 2.98 (26.35) | 2.98 (2.06) | 1.57 (-0.09) |
| Disturbance in attentionª | 19 | 7.05 (4.49-11.07) | 7.01 (98.01) | 7.01 (4.81) | 2.81 (1.14) |
| Product use complaintª | 19 | 31.41 (20-49.33) | 31.21 (554.76) | 31.16 (21.35) | 4.96 (3.29) |
| Drug interactionª | 18 | 2.33 (1.47-3.7) | 2.32 (13.57) | 2.32 (1.57) | 1.21 (-0.45) |
| Gamma-glutamyltransferase Increasedª | 18 | 16.05 (10.1-25.52) | 15.96 (252.27) | 15.95 (10.82) | 4 (2.33) |
| Hypothyroidismª | 18 | 12.1 (7.61-19.24) | 12.03 (182.05) | 12.02 (8.16) | 3.59 (1.92) |
| Confusional stateª | 17 | 2.16 (1.34-3.48) | 2.15 (10.51) | 2.15 (1.44) | 1.11 (-0.56) |
| Adverse eventª | 17 | 3.84 (2.38-6.18) | 3.82 (35.42) | 3.82 (2.56) | 1.93 (0.27) |
| Hyponatraemiaª | 17 | 6.21 (3.86-10.01) | 6.18 (73.91) | 6.18 (4.15) | 2.63 (0.96) |
| Neutropeniaª | 17 | 2.65 (1.64-4.27) | 2.64 (17.34) | 2.64 (1.77) | 1.4 (-0.27) |
| Vertigoª | 15 | 5.04 (3.03-8.37) | 5.02 (48.31) | 5.02 (3.28) | 2.33 (0.66) |
| Accidental exposure to productª | 14 | 3.49 (2.06-5.9) | 3.48 (24.71) | 3.48 (2.24) | 1.8 (0.13) |
| Hypercholesterolaemiaª | 14 | 34.2 (20.22-57.85) | 34.04 (448.24) | 33.98 (21.89) | 5.09 (3.42) |
| Paraesthesiaª | 14 | 1.8 (1.06-3.04) | 1.8 (4.95) | 1.8 (1.16) | 0.84 (-0.82) |
| Muscular weaknessª | 14 | 2.55 (1.51-4.31) | 2.54 (13.1) | 2.54 (1.64) | 1.35 (-0.32) |
| Febrile neutropeniaª | 13 | 4.2 (2.44-7.25) | 4.19 (31.6) | 4.19 (2.66) | 2.07 (0.4) |
| Dysgeusiaª | 13 | 3.46 (2.01-5.97) | 3.45 (22.65) | 3.45 (2.19) | 1.79 (0.12) |
| Hepatic enzyme increaseda | 13 | 4.13 (2.39-7.12) | 4.11 (30.65) | 4.11 (2.61) | 2.04 (0.37) |
| Gastrointestinal disorderª | 13 | 3.39 (1.97-5.85) | 3.38 (21.8) | 3.38 (2.14) | 1.76 (0.09) |
| Dehydrationª | 12 | 1.84 (1.05-3.25) | 1.84 (4.62) | 1.84 (1.15) | |
| Cognitive disorderª | 11 | 4.94 (2.73-8.93) | 4.92 (34.41) | 4.92 (3) | |
| Chillsª | 11 | 1.92 (1.06-3.48) | 1.92 (4.86) | 1.92 (1.17) | |
| Amnesiaª | 10 | 3.09 (1.66-5.76) | 3.09 (14.13) | 3.09 (1.84) | |
| Adrenocortical insufficiency acuteª | 10 | 125.51 (67.32-234.02) | 125.08 (1222.48) | 124.23 (73.76) | |
| General physical health deteriorationª | 10 | 1.94 (1.04-3.6) | 1.93 (4.51) | 1.93 (1.15) | |
| Alanine aminotransferase increasedª | 9 | 2.97 (1.54-5.71) | 2.96 (11.71) | 2.96 (1.71) | |
| Neurotoxicityª | 9 | 11.51 (5.98-22.15) | 11.48 (86.07) | 11.47 (6.63) | |
| Disorientationª | 8 | 4.04 (2.02-8.09) | 4.04 (18.27) | 4.03 (2.26) | |
| Ovarian cystª | 8 | 15.86 (7.92-31.75) | 15.82 (110.97) | 15.8 (8.84) | |
| Hepatocellular injuryª | 7 | 9.64 (4.59-20.24) | 9.62 (54.03) | 9.61 (5.17) | |
| Sleep disorderª | 7 | 2.16 (1.03-4.53) | 2.16 (4.34) | 2.16 (1.16) | |
| Insomnia | 7 | 0.53 (0.25-1.12) | 0.54 (2.83) | 0.54 (0.29) | |
| Electrocardiogram QT prolongedª | 7 | 4.1 (1.95-8.6) | 4.09 (16.35) | 4.09 (2.2) | |
| Hypogonadismª | 7 | 138.1 (65.59-290.76) | 137.77 (943.26) | 136.73 (73.34) |
Abbreviations: CI = confidence interval; EBGM = empirical Bayesian geometric mean; EBGM05 = the lower limit of the 95% confidence interval for EBGM; IC = information component; IC025 = the lower limit of the 95% confidence interval for IC; PT = preferred term; PRR = proportional reporting ratio; QT = Q-T interval; ROR = reporting odds ratio. a Statistically significant signals identified through disproportionality analysis.
Hypoadrenocorticism has been recognized in several clinical trials as an adverse event of particular concern. A significant as- sociation with endocrine system disorders is to be expected, as the drug interferes with hormone production.17 In addition, the neurological effects of mitotane may be underestimated in clinical practice. For example, a phase III clinical trial of mitotane for the treatment of low-grade localized ACC stated that 8 out of 42 subjects discontinued the drug due to adverse effects. At the same
time, hypoadrenocorticism occurred in 11 cases, and the inci- dence of neurological symptoms exceeded 20%,18 with dizziness or vertigo exceeding 50%. Studies have shown that when serum concentrations exceed 15-20 mg/L, patients frequently experience cognitive and neurological impairments, such as memory loss, confusion, and motor coordination issues.19,20 Maintaining mito- tane levels within the therapeutic range of 14-20 mg/L can help mitigate these neurotoxic risks, although individual tolerance
>360 DAYS
18.5%
37
181-360DAYS
15%
30
151-180 DAYS-
2.5%
5
121-150 DAYS-
5%
10
Percentage
91-120 DAYS
6.5%
13
0 Case number
61-90 DAYS
9%
18
31-60 DAYS-
9%
18
0-30 DAYS
34.5%
69
levels vary considerably.21 Our findings are consistent with pre- vious studies. Vigilant monitoring and management of these adverse effects is essential when taking mitotane for adrenocor- tical cancer.
The present study also identified several potential new adverse events not listed in the drug insert, which raises essential safety considerations. For example, significant signals of malignancy progression and ovarian cysts suggest that further studies are needed to assess these associations’ clinical relevance and causal- ity.22 Similarly, significant signals of QT interval prolongation sug- gest that routine cardiac monitoring may be required in patients treated with mitotane to detect and manage potential arrhythmias,
and unfortunately, there are still no definitive studies demon- strating the cardiotoxicity of mitotane.23
Subgroup analyses showed that the effects of mitotane on sex- ual function were gender-specific. Notably, men more commonly had hypogonadism and myasthenia gravis, whereas women had a higher incidence of ovarian cysts, balance disorders, and hyper- cholesterolemia.24 Ovarian cysts have been previously reported in small case series studies in more than half of women of child- bearing age following treatment with mitotane.25 Understanding this adverse effect of mitotane is of clinical significance, as ovarian cysts may cause significant psychological stress.26 This may guide us to pay special attention to women of childbearing age when
1.00
0.75
Adrenal Insufficiency
Cumulative incidence
Asthenia
Decreased Appetite
0.50
Diarrhoea
Dizziness
Fatigue
Malignant Neoplasm Progression
0.25
Nausea
- Off Label Use
0.00
0
1000
2000
days
| Drug | TTO (d) | Weibull distribution | |||
|---|---|---|---|---|---|
| Case reports | Median(d) (IQR) | Scale parameter: o. (95% CI) | Shape parameter: ฿ (95% CI) | Type | |
| 200 | 79 | 162.25 (132.19-192.32) | 0.58 (0.53-0.62) | Early failure | |
Abbreviations: CI = confidence interval; IQR = interquartile range; TTO = time to onset.
applying mitotane in the clinic. In younger patients under 18 years of age, adrenal and growth-related disorders are more prevalent, which supports the need for careful hormonal management in therapy,27 whereas, in older patients, fatigue and loss of appetite are the main focus of concern, as they have a significant impact on quality of life.
Multiple methods of imbalance analysis (proportional reporting ratio, reporting odds ratio, multi-item y Poisson Shrinker, Bayesian confidence propagation neural network) and sensitivity analyses were used in this study to improve the robustness of the results. The specificity of adverse reactions to mitotane was confirmed by the persistence of key adverse event signals, which were excluded by reports of coadministration. In addition, time-of-onset and Weibull distribution analyses showed that many of the adverse events occurred early in the treatment period, suggesting an ‘early failure’ pattern, which emphasizes the importance of proactive monitoring during the initial treatment phase.
Although this study provides valuable insights, there are some inherent limitations stemming from the FAERS database, such as under-reporting, reporting bias, and lack of causality confirmation. The voluntary nature of adverse event reporting may have resulted in data favoring more serious or novel events, and the lack of comprehensive clinical information (eg, dose, regimen, comorbid- ities) limited correction for confounding factors. Despite these limitations, the findings of this study provide important signals that may inform future prospective studies and guide clinicians in risk mitigation in mitotane therapy.
Conclusion
This study systematically analyzed adverse events associated with mitotane using the FAERS database, focusing on data since 2004. The findings not only confirmed known adverse reactions but also identified some potential risks not listed on the drug’s label. These results provide critical safety insights for clinicians when using mitotane to treat adrenocortical cancer and underscore the importance of closely monitoring patients throughout the treat- ment process.
Disclosure
The authors have no conflicts of interest to disclose.
Acknowledgement
We express our gratitude to the Department of Urology at the Second Affiliated Hospital of Nanchang University.
There were no specific funding sources for this research. We did not receive any external funding for this study.
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