Roflumilast is the first phosphodiesterase 4 (PDE4) inhibitor indicated for chronic obstructive pulmonary disease (COPD) in 2011, subsequently for plaque psoriasis approved by the U.S. Food and Drug Administration (FDA) and Health Canada [1, 2]. Notably, COPD has been found to be a complication of psoriasis [3]. T lymphocytes play an important role in the immunopathogenesis of both psoriasis and COPD, driving chronic inflammation [4, 5]. These two diseases impact millions of individuals worldwide and represent a huge economic burden [6, 7]. PDE4 expression is higher in patients with inflammatory conditions than in healthy people [8]. The PDE4 enzyme family (isoforms PDE4A-D) specifically catalyzes the hydrolysis of cyclic adenosine monophosphate (cAMP) [9]. Roflumilast elevates cAMP levels in inflammatory and immune cells to reduce the release of inflammatory factors, such as tumor necrosis factor α (TNFα), and interleukin (IL)-17, thereby improving hyperactive immune responses [10].

Phase III clinical trials have demonstrated good efficacy and tolerability profile of roflumilast [11, 12]. However, safety concerns could limit roflumilast’s clinical use [13]. Immune-related disease treatment is a prolonged procedure. Continuous safety monitoring is essential to fully understand roflumilast’s adverse events (AEs) during treatment [14]. Nevertheless, large-scale data analysis of roflumilast-related adverse reactions in the real world is still insufficient. An analysis based on the U.S. MarketScan database identified potential safety signals through investigating roflumilast’s concomitant medications [15]. Our study draws on FDA and Canadian pharmacovigilance databases, facilitating the capture of a broader spectrum of global AE reports, meanwhile, providing a novel perspective on signal detection that differs from prescription sequence analysis.

The FDA Adverse Event Reporting System (FAERS) and Canada Vigilance Adverse Reaction Database (CVARD) are spontaneous reporting databases that monitor post-marketing drug safety [16, 17]. To provide a clinical rationalization of drug administration, we conducted disproportionality analyses to identify potential AEs associated with roflumilast and systematically evaluated adverse reactions across different patient subgroups.

In this study, we systematically analyzed the real-world reports of roflumilast from 2011 Q1 to 2024 Q4 through the FAERS and CVARD databases. Analysis of patient characteristics revealed that the AE reporting rates were higher among the older adults (≥65 years) and oral administration population. The data suggested that similar counts of roflumilast’s adverse reaction reports were observed in males and females. Roflumilast-related AEs were reported most frequently in 2013, showing the first peak. This may be attributed to the Weber effect, which describes the characteristic pattern of spontaneously reported adverse reactions peaking within the first 2 years post-approval and subsequently declining [22]. While the second peak was in 2023, following its application for psoriasis. These results highlight the extensive clinical application of roflumilast and the requirement for surveillance.

We found some adverse reactions contained in the drug instructions, including diarrhea, nausea, decreased appetite, weight loss, headache, dizziness, insomnia, anxiety, depression, suicidal ideation and lung neoplasm malignant, which validated the reliability of our results. Our analysis identified distortional reporting of roflumilast-associated AEs that were not documented in the prescribing information, such as heart rate increased, tachycardia, palpitations, and condition aggravated.

The meta-analysis showed that AF was more frequent in the roflumilast group than in the placebo group (0.4% vs. 0.2%) [23]. An accelerated and irregular heart rhythm is the hallmark of AF, which can be non-symptomatic or cause symptoms like palpitations, increased heart rate, chest pain, nausea, dizziness, dyspnea, and general fatigue [24]. Immune remodeling is an important mechanism in AF which can increase the release of cytokines (e.g., IL-6) and exosomes by activating macrophages. In turn, pacing cardiomyocytes may further promote macrophage activation [25]. PDE4, a key factor in the regulation of heart rate, is able to alter cAMP concentrations of cardiac ryanodine receptor 2 microstructural domain. Likewise, the upregulation of PDE4-dependent cAMP levels in sinus node myocytes increases heart rate [26, 27]. It has been shown that administration of the high-dose PDE4 inhibitor rolipram significantly increased heart rate [28]. In chronic kidney disease, elevated levels of fibroblast growth factor 23 inhibited PDE4B expression in cardiomyocytes, further increasing sarcoplasmic reticulum Ca²⁺ leakage as well as promoting ventricular arrhythmias [29]. Roflumilast exacerbated tachycardia and hypotension in septic rats while improving renal perfusion and liver damage [30]. Notably, knockdown of PDE4D increased heart rate in hypertensive mice, helping them respond to β-adrenergic receptor stimulation of the sinus node normally [26]. The mechanisms by which roflumilast induces cardiac AEs like AF and palpitations are not yet fully understood, whereas animal studies suggest several potential pathways mediated by PDE4 inhibition. COPD or psoriasis patients who are experiencing hypertension may benefit from roflumilast medication. For patients with chronic nephritis and sepsis, blood pressure and electrocardiogram should be monitored regularly after applying roflumilast.

AEs that strongly associated with roflumilast were condition aggravated, chest pain, influenza-like illness, dyspnea, and cough, despite these actions being not labeled in the insert. Few studies have found the existence of the above five adverse actions. The DERMIS-2 trial observed that one case of psoriasis progression was reported in the topical roflumilast group [12]. In a randomized controlled trial utilizing oral roflumilast for the treatment of moderate-to-severe psoriasis, a non-ischemic chest pain event occurred at weeks 12–24 [31]. A pooled analysis showed that topical roflumilast caused upper respiratory tract infections [32]. CHEST guideline suggests that respiratory tract infections are a major cause of cough [33]. In a 16-week, randomized, double-blind, placebo-controlled trial, a lower number of serious AEs experienced in the roflumilast treatment group (n = 8), including COPD worsening, dyspnea, and influenza A virus. Meanwhile, cough belonged to mild-to-moderate side effect [34]. Although the exact mechanism of exacerbations during roflumilast treatment remains unknown, we hypothesize that it might be connected to the dual effects of cAMP, which reduces T cell proliferation by facilitating the release of IL-10. However, higher dosages of roflumilast caused bone marrow-derived dendritic cells to elevate PDE4B and PDE4D expressions in response to increased cAMP levels. The result was followed by Th17 cell polarization and high expression of IL-23 that stimulated the release of IL-17 and IL-6 [35]. It is crucial to monitor the changes of inflammatory cytokine levels before and after the clinical application of roflumilast, considering the prognosis and quality of life of patients. Physicians should timely detect and assess exacerbation, chest pain, and respiratory dysfunctions in roflumilast-treated patients. Depending on the situation, adjusting the therapeutic dosage, the combination of medications, or symptomatic supportive therapy may be required.

Multiple clinical trials demonstrated that the roflumilast-related predominant AEs involved the gastrointestinal and psycho-neurological systems, as well the majority of AEs were transient and mild-to-moderate in severity. Long-term treatment of roflumilast in COPD or plaque psoriasis revealed higher incidence rates of diarrhea, nausea, headache, and insomnia than placebo [1, 36]. An analysis of 15 trials involving 11,168 COPD subjects found higher incidences of psychiatric-related adverse reactions in roflumilast 500 μg group than those in the control group (OR 2.13, 95% CI: 1.79–2.54), particularly an increased possibility of sleep disorder, anxiety, and depressed mood. Notably, participants receiving roflumilast reported 3 cases of suicidal behavior and 2 suicide attempts, whereas no related behaviors were noted in placebo-treated participants. No statistically significant difference was observed in psychiatric AEs between the 250 μg roflumilast and placebo groups (OR 0.87, 95% CI: 0.56–1.33) [37]. Although nervousness and sleep disorders are not listed in the FDA-approved labeling while being included in Canadian labels, their identification in our real-world data illustrates the dynamic nature of drug safety knowledge, which in turn underscores the importance of ongoing, systematic pharmacovigilance to capture and validate safety signals across diverse information sources.

Present studies have found that the regulatory role of PDE4 in gastrointestinal systems strongly associated with common AEs, such as nausea and diarrhea. The following postulated mechanisms may contribute to these two AEs. There is evidence that nausea is closely connected to delayed stomach transit. Roflumilast inhibited gastric transit more effectively than selective PDE4B inhibitors, but PDE4 inhibitor-induced gastroparesis wasn’t influenced by gene deletion of any one PDE4 subtype, illustrating that two or more PDE4 subtypes may be involved in this condition. Mechanistically, roflumilast-induced PDE4D inhibition may contribute to diarrhea through the signals of cystic fibrosis transmembrane conductance regulator and 5-hydroxytryptamine 4 receptor [38]. Animal research revealed that a prolonged overdose of roflumilast led to diarrhea, as well as increasing serum levels of cytokine-induced neutrophil chemotactic factor 1 and leucocytes. Diclofenac, a non-selective cyclooxygenase inhibitor, could protect against the toxic effects mentioned above by roflumilast [39]. Therefore, taking diclofenac helps patients improve roflumilast-induced diarrhea and abdominal pain. Anti-diarrheal drugs like oral rehydration salts can be used to treat dehydration induced by severe diarrhea. In addition, roflumilast inhaler is being developed to avoid gastrointestinal problems [40].

PDE4 also plays a critical role in the central nervous system. When compared to wild-type (WT) mice, PDE4A KO or PDE4B KO mice proved anxiety characteristics along with higher corticosterone levels, while PDE4B KO mice also showed increased long-term depression [41–43]. Furthermore, PDE4D KO mice slept for a shorter time than their WT littermates under xylazine/ketamine-induced anesthesia [44]. The above mechanistic hypothesis could be the reason for induction of insomnia, sleep disorder or vomiting with roflumilast. Thus, physicians should proactively inquire about the patient’s psychological history or conduct a psychological examination before prescribing roflumilast. To lower the patient’s risk of adverse mental events, dose reduction or gradual dose escalation should be considered.

In our study, there were only a limited number of reports regarding AEs associated with cancer. Reports of cancer in clinical trials were consistently rare and not considered to be directly caused by roflumilast [1]. Recent research has indicated that roflumilast may inhibit the proliferation of liver and ovarian cancer cells [45, 46]. However, PDE4-dependent cAMP was also found to suppress both innate and adaptive immunity, which could potentially facilitate immunological escape. Evidence suggested that roflumilast increased the volume of B-cell lymphomas while decreasing CD3⁺ cell and CD4/CD8 ratios, indicating its potential immunosuppressive properties. Specifically, inhibition of PDE4 enhanced cytokines (IL-10, IL-8, and IL-6) gene transcription through activation of the cAMP/PKA/CREB signaling pathway. These cytokines subsequently bond to their respective receptors in an autocrine manner, further phosphorylating JAK/STAT signaling and elevating transcription as well as surface expression levels of the immune checkpoint PD-L1 [47]. The aforementioned speculative mechanisms for roflumilast-associated malignancies require validation with additional clinical samples. Despite the ongoing debate on roflumilast’s carcinogenic potential, close surveillance of cancer-related AEs in clinical practice is indispensable.

Roflumilast plasma concentrations were similar among children, adolescents, and adults; however, gender and age were found to influence roflumilast clearance and metabolic fraction in vivo. A pharmacokinetic study of roflumilast revealed higher total PDE4 inhibitory activity in female and older patients with COPD [48, 49]. Multivariate analysis of Korean patients revealed that older age was significantly associated with higher rates of roflumilast treatment withdrawal [50]. Thus, it was considered that drug discontinuation is more likely to occur in females and the older adults. In terms of gender, females were prone to develop AEs such as nausea, headache, and back pain. Notably, males were more inclined to AF and suicide attempt. This could be attributed to males having higher hazards of AF and suicide [51]. So as to properly manage and intervene with side effects, it is crucial to consider age and gender differences into account when evaluating drug safety. Females and the older adults should also pay special attention to the reasons for roflumilast discontinuation.

Psoriasis has been approved for topical treatment with roflumilast cream [36]. Clinical trials treating oral roflumilast for psoriasis have been shown equally excellent safety and tolerability. Similarly to the analysis of a randomized controlled trial, our study thought that headache was the most common AEs in the topical group. It was worth noting that decreased weight was more prevalent in the oral roflumilast group [2, 31]. In phase II clinical trials, topical roflumilast caused minimal weight change in patients with psoriasis [52]. Studies have shown that roflumilast may help obese patients decrease weight by inhibiting adipogenesis and promoting lipolysis through AMPKα activation [53]. A multicenter study showed that patients with low body mass index (BMI <23 kg/m²) were more likely to experience adverse reactions and then choose to discontinue treatment with roflumilast [13]. Therefore, patients with BMI <23 kg/m² must be cautious with roflumilast or even avoid choosing an oral dosage form. But if applying the topical formulation of roflumilast, concern should be taken to deal with headache, drug ineffective and dermatologic manifestations that haven’t yet been listed on the label (e.g., burning sensation, exfoliation, and discoloration).

For TTO analysis, only 16.7% reports of roflumilast-related reports in the FAERS database were usable. Based on the available TTO data, 60.1% reports occurred within the first month after initiating therapy. Previous studies similarly found that AEs associated with oral roflumilast occur in the first 4 weeks, whereas roflumilast cream-associated AEs were usually reported in the first 2 weeks after treatment [12, 54]. Long-acting bronchodilators such as long-acting β₂-agonists and long-acting muscarinic antagonists, which together with inhaled corticosteroid are the basic drugs for long-term management of COPD. Whether used as monotherapy or combination therapy (e.g., dual or triple therapy), roflumilast has demonstrated the greatest benefit in patients with moderate-to-severe COPD [11, 55]. More efficiently than either medication alone, formoterol and roflumilast combination prevented LPS-induced production of TNFα and chemokines that recruited monocytes and T cells in human bronchus model in vitro [56]. Finally, we performed sensitivity analyses to identify side effects influenced by roflumilast alone, especially gastrointestinal issues, psychological disorders, pulmonary conditions and heart problems. These AEs may challenge patients’ medication adherence and compromise the effectiveness of roflumilast.

This research is the most comprehensive in-depth, and detailed pharmacovigilance study of roflumilast-related AEs depending on two databases. Nevertheless, it is crucial to acknowledge the limitations of this study. First, the databases have inherent limitations, such as under-reporting, reporting bias, and incomplete data. Under-reporting may occur due to patients’ lack of reporting awareness or clinicians’ failure to identify events. Reporting bias can stem from the inconsistent understanding of reporters, obstructing an accurate evaluation of roflumilast’s safety profile. Additionally, incomplete report details may reduce representativeness and introduce selection bias, which necessitate cautious interpretation of findings like TTO. Second, there are confounding variables in the study. Although this study only selected primary suspected drugs for analysis and conducted sensitivity analyses to exclude concomitant medications, potential confounding variables (e.g., duration of use, comorbidities, demographic variations) may affect the accuracy of the results and hinder stratified assessments based on patient characteristics. Third, signal detection in pharmacovigilance primarily provides associative information, estimating signal strength rather than establishing a definitive causal relationship between roflumilast and AEs. Confirming causality requires further real-world validation, including large-scale prospective cohort studies, electronic health record-based case-control studies, and mechanism-based research (animal models and cell experiments) to verify causality and clarify biological mechanisms. Despite the above limitations, the cross-validation approach using the FAERS and CVARD databases still provides valuable insights and guidance for the post-marketing safety monitoring and rare signal detection of roflumilast.

This study conducted a comprehensive analysis of roflumilast-associated AEs reported in the FAERS and CVARD databases. Our analysis identified disproportional reporting of several labeled risks while detecting novel safety concerns. Valuable risk suggestions were provided for different populations through subgroup analysis. The findings emphasize that individualized evaluation of patient characteristics and comorbidities before prescribing roflumilast is a key strategy for risk mitigation and rational pharmacotherapy.