Multidimensional assessment of adverse events of finasteride：a real-world pharmacovigilance analysis based on FDA Adverse Event Reporting System (FAERS) from 2004 to April 2024

Androgenetic alopecia (AGA), commonly referred to as male-pattern baldness, is characterized by hair loss driven by dihydrotestosterone, a potent derivative of testosterone [1]. It has a significant negative physiological and psychological impact on patients. Patients with AGA experience adverse effects such as sexual dysfunction, affective disorders, stigma and low self-esteem compared to normal individuals [2,3], especially in younger patients [4]. Fortunately, however, since receiving approval for treating AGA in 1997, finasteride has gained popularity for AGA treatment and has shown positive therapeutic outcomes [5].

Finasteride, as the main drug for the treatment of AGA, works by efficiently inhibiting 5-alpha reductase inhibitors (5-ARIs) [6]. Since the synthesis of sex hormones in the body is dependent on steroid reductases, and SRD5A2 is a biofilm chimeric steroid in the class of steroid reductase enzymes, SRD5A2 can synthesize dihydrotestosterone by catalyzing the reductive reaction of testosterone, which can lead to the onset of AGA if it is too high [7]. So finasteride as 5-alpha reductase inhibitor is the anti-androgenic drug that is used to treat both diseases and is widely available [8]. It is noteworthy that patients with Benign prostatic hyperplasia and AGA experience AEs of depression or suicide when neuroactive steroids have a reduced ability to control mood, behavior, and cognition [9–11]. The data show that between 1998 and 2008, an estimated 4.6 million men were treated with at least 1 mg of finasteride [12]. More importantly, as of June 2021, the FDA AE disclosure data have reported up to 10,295 serious AEs with finasteride use. Unfortunately, however, safety information regarding finasteride in patients with AGA primarily stems from clinical trials and post-marketing observational studies. The frequency of persistent AEs associated with it remains unclear, underscoring the necessity for additional evidence-based research to investigate the potential risks of finasteride use [13]. A Real-world study, with their large data samples and rigorous inclusion and exclusion criteria, have emerged as a useful tool to explore AEs and to compensate for clinical trials. An effective way of exploring adverse drug events and bridging the gap between clinical trials to provide us with evidence-based information.

FAERS is an openly available database created by the FDA that gathers instances of adverse drug events reported globally, with a large amount of real-world data and extensive geographic coverage of records of AEs from practicing physicians, pharmacists, registered nurses, consumers, and other healthcare professionals, among others [14,15]. Being the largest pharmacovigilance database globally, FAERS is an invaluable resource for identifying AEs associated with drug usage [16]. Thus, the objective of this study was to assess the long-term safety profile of finasteride following its market introduction using data extracted from FAERS database [17]. This study offers guidance and citations for the rational and safe clinical administration of finasteride dosage.

To our knowledge, earlier studies on finasteride safety have primarily been confined to clinical trials or concentrated on particular AEs, such as sexual dysfunction, and have mainly investigated potential safety concerns [34–36], whereas our study discusses this more fully and extensively. Although in a large real-world drug study in 2017 it comprehensively and systematically summarized global reports of finasteride-associated sexual dysfunction in FAERS, we offered a more precise and comprehensive description and identification of AEs associated with finasteride. Although the incidence of AEs reported in clinical trials was low, the risk of occurrence of finasteride-associated AEs still exists, necessitating further studies and additions to the literature.

With regard to ‘reproductive system and breast disorders’, sexual dysfunction is the most significant adverse effect of finasteride treatment in young men with AGA, manifested by loss of libido and erectile dysfunction [37]. Moreover, the distribution of medication-related AEs indicated that the highest number of cases (3146 27.22%) were in the age group of 18-45 years, and in the younger age group even a low dose of finasteride (1mg) may lead to persistent sexual dysfunction in young males, which may increase the risk of suicide [38]and persist after discontinuation of the medication [8]. This may be due to the fact that younger patients have more stressful lives, are more sensitive to hormonal changes than older adults [39], are more prone to symptoms, and are more susceptible to the adverse effects of finasteride. These two adverse effects further confirm the existing knowledge about the potential adverse consequences of finasteride on sexual functioning and the increased risk of suicide [40]. It was found that an increased risk of suicide may exist with finasteride in the treatment of men with a history of psychological disorders [41]. Surprisingly, the 2023 Treatment Update for AGA shows that suicide and depression in patients with AGA may be caused by sexual dysfunction (erectile dysfunction, hypospermia, neurological dysfunction), a side effect of finasteride (1mg once daily) [42]. Therefore, comprehensive and precise clinical screening for the drug and close monitoring of patients for post-drug adverse effects are warranted.

With regard to the ‘psychiatric disorders’, psychological distress in patients with AGA has become a significant motivator in the development of effective treatments and the reduction of adverse effects of medication [43]. There is a risk of suicide, depression, and anxiety in patients younger than 40 years of age treated with finasteride for alopecia areata [44], which may be related to the involvement of 5-ARIs in the central nervous system’s synthesis of neuroactive steroidal organisms [45]. Neurosteroids are important physiological regulators of neural function in the adult brain and are involved in the control of the neuroendocrine system of reproduction [46]. A small human study observed depressive symptoms associated with reduced levels of neurosteroids in the cerebrospinal fluid of men who were taking finasteride [47]. This observation was supported by animal studies [48,49]. A study has been conducted by evaluating FMRI and HPLC-mass spectrometry analyses of neurosteroid levels in cerebrospinal fluid, pointing to the fact that finasteride disrupts neurotransmitters and chemical messengers [50]. These findings reinforce that anxiety and depression induced by finasteride use cannot be ignored. However, it has been suggested that the results of disproportionate analyses of AE signals may be influenced by the susceptibility of young patients to adverse factors, and further sensitivity analyses have shown an association between AGA and psychological AEs in young people that is not due to drug use [51]. This is consistent with the fact that pharmacovigilance does not directly prove biological causation. Emerging evidence also suggests that finasteride inhibits glioblastoma proliferation [52]. These findings highlight the potential relevance of finasteride to neuroscience and the need to closely monitor neurological psychiatric problems in patients receiving finasteride.

With regard to ‘renal and urinary disorders’, the only PT’s with positive signals were post micturition dribble and terminal dribbling, the former of which is the most frequent adverse reaction in men. Traish suggests that the symptoms are due to a novel tissue-specific androgen deficiency that develops when finasteride inhibits the enzyme 5-alpha reductase, which reduces the biosynthesis of 5alpha-dihydrotestosterone [53]. The symptoms of post micturition dribble have been shown to be associated with the development of a new form of androgen deficiency in men. In addition, finasteride has been widely used in the treatment of a variety of testosterone-related disorders, and new evidence suggests that finasteride has a protective effect on testosterone-induced calcium oxalate crystals, which is effective in preventing the formation of calcium oxalate-type renal stones and neutralising the calcium oxalate-promoting effects of testosterone [54]. Future studies could explore the relationship between finasteride and testosterone levels, and reduce the prevalence of renal stones in patients with high levels of the testosterone.

At the PT level, we discovered that while prostate pain, prostate calcification, and prostate atrophy were notable in disproportionate assessments and identified as adverse reactions by certain studies, they were regarded as treatment indications in Table 1, consistent with findings from another research. Although finasteride reduces the risk of prostate cancer, it increases the malignancy of high-grade prostate cancer [55]. To ensure the reliability of our results, we omitted adverse reactions listed as indications in Table 2.

In addition to the expected AEs associated with finasteride use, our study identified a number of unintended AEs not mentioned in the specification that need to be further analyzed and evaluated, including ‘Peyronie’s disease’, ‘post-5α reductase inhibitor syndrome’, ‘catastrophic reaction’ and “thermophobia”. Peyronie’s disease is a male condition characterized by penile curvature, pain, penile shortening and erectile dysfunction [56]. This is an unintended AE associated with AGA treated with finasteride (176/210 83.8%) [57]and the results of our study are consistent with the above studies. In addition, a case report found that the pathogenesis of finasteride-treated AGA is the same as that of Peyronie’s disease, in that inflammation affects the penile leukomalacia, leading to the formation of inelastic microtissue that deforms the penis [58,59]. However, the relationship needs to be further determined [57]. Another specification unmentionable AE that appeared in our analysis was the post 5-alpha-reductase inhibitor syndrome, 5-ARIs are drugs used to treat androgen-dependent diseases. Long-term use of 5-ARIs in patients with AGA leads to persistent side effects known as post-finasteride syndrome (PFS) [60,61]. PFS is also characterized by symptoms of penile shortening and penile curvature [62]. Not only this, but also persistent or irreversible sexual, neurological, physical and psychiatric side effects [63]. Leliefeld et al. have demonstrated that finasteride, a 5α-reductase inhibitor, inhibits the conversion of testosterone to 5α dihydrotestosterone (DHT) in the prostate and scalp and impairs the levels of other neurosteroids in the brain, demonstrating that sustained changes in androgen receptor and neurosteroid levels are associated with PFS [64]. However, previous studies have been inconclusive as to whether or not PFS exists [65]. Finally, our study reinforces the need for additional clinical research to assess the balance between the health risks and benefits of the medication. Careful consideration is required when using finasteride and developing potential new therapeutic options for treating these two conditions.

There is no mention of the adverse reaction in the insert: male breast cancer in the FAERS database or in the previous literature. As for the rare adverse reaction in the specification: hypersensitivity reaction, there was one case report of a patient with prostatic hyperplasia who developed maculopapular rash and rash on the extremities after 2 months of drug administration [66]. According to the FAERS database, SOCs not mentioned in the specification included endocrine system diseases, renal and urinary system diseases, various surgical and medical operations, and various congenital familial hereditary diseases. It should be noted that we conducted a revalidation of the results of the specification from a pharmacovigilance perspective for reproductive and breast disorders, psychiatric categories, and various neurological disorders. There is emerging evidence that finasteride both treats suppurative sweats in women [67] and reduces the incidence of bladder cancer [68,69]and induces type 2 diabetes [70], down-regulates androgen receptor expression in the renal cortex [71], forms blood clots [72], and alters intestinal microbial abundance [73,74] among other things. With regard to ‘endocrine disorders’ and ‘renal and urinary disorders’ it is noteworthy that almost all clinical trials did not include primary and secondary endpoint sensitisers for type 2 diabetes mellitus, renal dysfunction indicators. These unintended AEs raise concerns about the effects of finasteride on endocrine and renal disorders and the potential risk of severe endocrine disorders [75]. Further studies are necessary to investigate the prevalence of hormonal and metabolic changes and to evaluate the level of risk for individuals taking finasteride.

With respect to the timing of AEs and final outcome, the probability of AEs was greatest on days 0-31 of finasteride use in our analysis. Therefore, it is important to closely monitor potential risks associated with medication use over a one-month period. However, it is also possible that patients linked and reported their medication side effects within a short period of time after using the drug, which could also lead to bias in the data set. In addition, disability and life-threatening events such as male reproductive tract hypoplasia and catastrophic reactions were also reported in our study, suggesting that comprehensive monitoring and management of AEs receiving finasteride medication should not be underestimated, especially in the treatment of male patients with AGA and prostatic hyperplasia [76].

From the perspective of sex subgroups, male patients reported a higher incidence of AEs with finasteride compared to female patients. This sex difference can be understood from both sociological and biological perspectives. From the sociological point of view, firstly, the prevalence of AGA is on the rise globally, with 45.72% of men and 5.05% of women [77]. Furthermore, premenopausal women suffering from hair loss are mainly treated with minoxidil, oral contraceptives, and cosmetic products [78]. Finasteride, on the other hand, has been used to promote hair growth mainly after menopause [79,80]. As a result, the population of women who use finasteride is relatively small. Secondly, women prefer hair transplants and cosmetics to increase scalp hair fullness [81]. Finally, the safety of oral finasteride in patients with a history of gynaecological malignancy has not yet been clarified, which makes the use of this drug in the treatment of AGA more limited, especially when compared to male patients [82]. Biologically, AGA, previously thought to have an autosomal dominant mode of inheritance, has a reduced epistasis in females [83],this makes males more susceptible to AGA than females [84]. Furthermore, female follicle levels of type I and type II 5α-reductase and androgen receptors are half those of males. The percentage of females with a clinical diagnosis of AGA is then lower than that of males. In summary, we hypothesize that men experience more AEs than women because of the aforementioned biological and sociological factors, and further investigation into the underlying mechanisms and reasons is warranted.

At the age subgroup level, our study found that patients aged 18-65 years were more likely to report AEs involving finasteride than patients aged < 18 years and those patients aged ≥ 65 years. Because of the high correlation between AGA severity and age factors [85], AGA not only affects social functioning and emotional well-being in young men [86], but also affects sexual functioning and reduces quality of life in women aged 18-65 years [87]. Therefore, clinicians can kindly remind patients aged 18-65 years of the medication precautions when using it in the clinical setting, so that finasteride AEs will not go unnoticed in the non-medical setting.

It is crucial to recognize some constraints of our research, primarily arising from the fundamental features of pharmacovigilance databases. Firstly, up to 53.67% of the reports in our study originated from consumers (n = 6203), given the potential for inaccurate or misleading content in reports submitted by non-medical professionals due to limitations in their medical knowledge. Second, our data analyses failed to cover a wide range of unquantified confounding variables that may affect AEs, such as potential drug interactions, changes in treatment regimens, and results of laboratory tests and instrumental examinations. Additionally, the FAERS database is subject to incomplete or inaccurate data, particularly regarding drug therapy duration. Missing information on treatment cessation and adherence may impact the timing of AEs. Finally, further prospective studies are needed to confirm and clarify the relationship between finasteride and these AEs, addressing issues like data inconsistency and confounding factors.

We performed pharmacovigilance analyses using actual data from the FAERS database, and the adverse reactions identified in the survey were generally consistent with those in the package inserts. Additionally, we detected AEs not listed in the specifications, including post 5-alpha-reductase inhibitor syndrome, Peyronie’s disease, testicular microlithiasis, and catastrophic reactions. The identification of these strongly indicating AEs supplements the inherent limitation of the relatively small sample size in clinical studies of this drug. The results of this study help to inform the safe and rational use of the drug in the clinic.

We would like to thank the participants and researchers of the FAERS database. We also acknowledge Medex UIMA 1.8.3 system for providing their platforms and contributors for uploading meaningful data.

All relevant data are within the paper and its Supporting Information files.

The author(s) received no specific funding for this work.