Post-marketing safety of solriamfetol: A retrospective pharmacovigilance study based on the us food and drug administration adverse event reporting system

Lingling Wu; Kaijian Zhu

doi:10.1371/journal.pone.0333130

. 2025 Sep 22;20(9):e0333130. doi: 10.1371/journal.pone.0333130

Post-marketing safety of solriamfetol: A retrospective pharmacovigilance study based on the us food and drug administration adverse event reporting system

Lingling Wu ^1,², Kaijian Zhu ^1,^2,^*

Editor: Christian Veauthier³

PMCID: PMC12453233 PMID: 40982454

Abstract

Purpose

Excessive daytime sleepiness (EDS) seriously affects quality of life and may increase the risk of life-threatening situations, such as motor vehicle accidents. Solriamfetol is a novel medication approved for the treatment of EDS and serves as an alternative to traditional stimulants. This retrospective pharmacovigilance study aimed to analyze adverse events (AEs) related to solriamfetol based on real-world data.

Methods

Data regarding solriamfetol-related adverse events were retrieved from the FDA Adverse Event Reporting System (FAERS) from Q3 of 2019 to Q1 of 2024. A total of 1550 reports on solriamfetol-related AEs were analyzed using disproportionality analysis to identify AE signals across various organ systems.

Results

A large proportion of AEs were reported among female patients (64.06%), primarily including those with narcolepsy (38.13%) and obstructive sleep apnea (3.68%). The most frequently reported AEs included headache, anxiety, and drug ineffectiveness, with 46.8% of AEs occurring within 7 days of treatment initiation. Furthermore, solriamfetol was significantly associated with psychiatric and nervous system disorders as well as cardiac and general disorders.

Conclusions

Solriamfetol-related adverse events were mainly psychiatric, neurological, cardiac, and general disorders, with headache, anxiety, and drug ineffectiveness being the most common. Nearly half of the events occurred within the first week of treatment. Given the limitations of the FAERS database, further prospective studies are needed to confirm these findings.

Introduction

In sleep medicine consultations, individuals often present with excessive daytime sleepiness (EDS), defined as the inability to stay awake during the normal wake period, which may manifest as persistent drowsiness, difficulty staying awake in monotonous situations, automatic behaviors, and impaired sustained attention or vigilance [1,2]. According to recent epidemiological studies, the prevalence of EDS is as high as 33% among adults, and in children and adolescents, the prevalence of EDS is as high as 29.2% [3,4]. EDS significantly reduces the quality of life of patients, leading to decreased productivity, impaired learning, poor concentration, and memory loss [5]. In addition, it has been shown to increase the incidence of several chronic diseases, including cardiovascular events and diabetes [6,7].

The management of EDS involves addressing underlying causes and implementing both non-pharmacologic and pharmacologic strategies. Behavioral interventions such as scheduled napping, sleep hygiene education, and work accommodations may offer partial relief [1]. However, pharmacologic treatment plays a crucial role, particularly for patients with narcolepsy or those with obstructive sleep apnea (OSA) who continue to experience EDS despite effective continuous positive airway pressure therapy. In such cases, medication becomes an essential component of care to improve wakefulness and quality of life [8].

For narcolepsy-related EDS, FDA-approved medications include modafinil, armodafinil, methylphenidate, amphetamine derivatives, sodium oxybate, solriamfetol, and pitolisant [9]. In contrast, pharmacologic options for residual EDS in patients with OSA are more limited, with modafinil, armodafinil and solriamfetol approved in the United States, and only solriamfetol also approved in the European Union for this indication [10]. Moreover, these drugs may have adverse effects, including headache, nausea, dry mouth, anorexia, and diarrhea [9]. In some patients, the use of these drugs alone or in combination may be ineffective [11]. This ineffectiveness can lead to overdose or repeated use of the drugs, resulting in addiction. Therefore, the use of the aforementioned drugs is limited in clinical settings [12].

Solriamfetol was first approved in the United States of America in March 2019 and subsequently approved in the European Union for the treatment of EDS caused by narcolepsy or OSA [13]. Solriamfetol selectively binds to dopamine and norepinephrine transporters and inhibits the reuptake of the two neurotransmitters without promoting monoamine release [14]. It is highly bioavailable, has a weak correlation with eating habits, and can achieve the desired therapeutic effect at a certain dose, which may improve the adherence of patients to treatment [15]. A randomized, double-blind trial of solriamfetol showed no serious adverse events after overdose, demonstrating the safety of the drug [16].

Despite the favorable therapeutic effects of solriamfetol in clinical settings, its side effects cannot be neglected. In a phase 3 clinical trial, the solriamfetol group had a higher incidence of adverse events than the placebo group [17]. Although many clinical trials have investigated solriamfetol-related adverse events, the results require further validation owing to relatively small sample sizes and limited follow-up durations. The FDA Adverse Event Reporting System (FAERS), one of the largest pharmacovigilance databases, assists the FDA in monitoring the safety of drugs and therapeutic products once they have been approved for clinical use [18]. The FAERS database, which is regularly updated, contains authentic reports of drug-related adverse events from various sources, including medical professionals, consumers, and manufacturers. Given the extensive use of solriamfetol worldwide and the limited assessments of its associated AEs, we comprehensively analyzed the system-specific side effects of solriamfetol in this study, aiming to provide a reference for clinical practice.

Materials and methods

Data sources and mining

This retrospective pharmacovigilance study was performed using data from the FAERS database from the third quarter of 2019 to the first quarter of 2024. The participant selection methodology is illustrated in Fig 1. The FAERS database collects adverse event reports from healthcare professionals, consumers, and manufacturers. As a spontaneous reporting system, it is subject to several inherent limitations, including reporting bias, underreporting, and the absence of detailed clinical information such as dosage, treatment duration, and patient comorbidities. Additionally, causality between solriamfetol and adverse events cannot be established, as reports are not systematically verified [19]. Given that the FAERS database is based on voluntary reporting, the presence of duplicate entries is likely. Therefore, we screened the raw data and removed all duplicate entries. We selected “solriamfetol” as the target drug and designated it as the primary suspect (PS) in the drug role code within the dataset. This study adhered to the principles of the Declaration of Helsinki and was conducted according to the relevant guidelines. Our study protocol was reviewed and approved by the Research Ethics Committee of Huaian Fifth People’s Hospital (No.KY-P-2024-031-01). The consents were waived by the Research Ethics Committee of Huaian Fifth People’s Hospital. Since the FAERS database is accessible to the public and patient records are anonymized and de-identified, informed consent are not required for this study. Adverse events (AEs) were coded using the Preferred Terms (PTs) from the Medical Dictionary for Regulatory Activities (MedDRA, version 25.0). AEs and their categories were classified as PTs and System Organ Classes (SOCs), respectively. The time to onset of AEs was defined as the time interval between the initiation of solriamfetol treatment and the occurrence of AEs.

Statistical analysis and signal detection

Disproportionality analysis is widely used to investigate the potential relationship between drugs and their AEs. In this study, the R software (version 4.1.0) was used to statistically assess disproportionality signals. Four statistical methods, namely, the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS), were used to identify potential associations between solriamfetol and its AEs based on the disproportionality analysis framework. The specific equations and criteria for these four methods are detailed in S1 Table. These methods were used to detect potential AE signals. A positive signal was considered when the criteria of all four methods were met.

Results

Descriptive analysis

From the third quarter of 2019 to the first quarter of 2024, a total of 20,816,909 AEs were reported in the FAERS database. After duplicates and incomplete data were excluded, a total of 1550 reports involving 3012 AEs mentioned solriamfetol as the PS. Annual changes in the reported solriamfetol-related AEs are shown in Fig 2, and the clinical characteristics of these AEs are summarized in Table 1. Notably, the proportion of women (993, 64.06%) was higher than that of men (408, 26.32%) in the included AE reports. As shown in Table 1, the most frequently reported indication for solriamfetol was narcolepsy (596, 38.13%), followed by OSA (57, 3.68%). The median age of patients was 40 years; however, age data were unavailable for approximately 78% of cases. Hospitalization (38, 12.97%) was the most frequently reported serious outcome. Most AE reports were from the United States (1403, 90.52%), followed by France (52, 3.35%) and Germany (27, 1.74%). Consumers were the primary reporters (825, 53.23%), followed by physicians (421, 27.16%). In terms of the reporting timeline, the year with the highest number of AE reports was 2022 (549, 35.42%), followed by 2021 (416, 26.84%), 2020 (295, 19.03%), and 2023 (236, 15.23%).

Fig 2 — Abbreviations: AE, adverse event.

Table 1. Basic information of solriamfetol-related AE reports retrieved from the FAERS database (from third quarter of 2019 to the first quarter of 2024).

Characteristics of patients	Reports, n (%)
Sex
Female	993 (64.06)
Male	408 (26.32)
Unknown	149 (9.61)
Age in years
< 18	9 (0.58)
18–45	198 (12.77)
45–65	117 (7.55)
≥ 65	22 (1.42)
unknow	1204 (77.68)
Indications
Narcolepsy	591 (38.13)
Obstructive sleep apnea syndrome	57 (3.68)
Unknown	902 (58.19)
Serious outcomes
Hospitalization	38 (12.97)
Death	5 (1.71)
Life-threatening outcomes	5 (1.71)
Disability	4 (1.37)
Other serious outcomes	241 (82.25)
Reporter
Consumer	825 (53.23)
Physician	421 (27.16)
Pharmacist	242 (15.61)
Unknown	62 (4.00)
Reported countries (Top 3)
United States	1403 (90.52)
France	52 (3.35)
Germany	27 (1.74)

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SOC signals

The signal strengths of AEs at the SOC level are presented in Table 2. The results showed that solriamfetol-induced AEs affected 23 organ systems. The significant SOCs associated with solriamfetol-induced AEs, in which at least one of the four statistical methods (ROR, PRR, BCPNN, and MGPS), included psychiatric disorders (SOC: 10037175); pregnancy, puerperium, and perinatal conditions (SOC: 10036585); nervous system disorders (SOC: 10029205); general disorders and administration site conditions (SOC: 10018065); and cardiac disorders (SOC: 10007541).

Table 2. Signal strengths of solriamfetol-related AEs at the SOC level in the FAERS database.

System organ class	N	ROR (95% CI)	PRR (95% CI)	χ2 statistic	IC (IC025)	EBGM (EBGM05)
Psychiatric disorders	520	3.49 (3.18, 3.84)	3.06 (2.83, 3.31)	765.34	1.61 (1.48)	3.06 (2.83)
Pregnancy, puerperium, and perinatal conditions	26	2.38 (1.62, 3.5)	2.37 (1.6, 3.51)	20.57	1.24 (0.7)	2.37 (1.71)
Nervous system disorders	396	1.84 (1.66, 2.05)	1.73 (1.57, 1.91)	132.85	0.79 (0.64)	1.73 (1.59)
General disorders and administration site conditions	808	1.63 (1.5, 1.76)	1.46 (1.38, 1.55)	142.58	0.54 (0.43)	1.46 (1.36)
Cardiac disorders	91	1.5 (1.22, 1.85)	1.48 (1.22, 1.8)	14.59	0.57 (0.27)	1.48 (1.25)
Endocrine disorders	12	1.46 (0.83, 2.58)	1.46 (0.83, 2.58)s	1.75	0.55 (−0.24)	1.46 (0.91)
Immune system disorders	44	1.2 (0.89, 1.62)	1.2 (0.89, 1.61)	1.51	0.27 (−0.16)	1.2 (0.94)
Investigations	160	0.87 (0.74, 1.02)	0.88 (0.75, 1.03)	2.82	−0.19 (−0.41)	0.88 (0.77)
Ear and labyrinth disorders	11	0.85 (0.47, 1.54)	0.85 (0.47, 1.53)	0.28	−0.23 (−1.05)	0.85 (0.52)
Vascular disorders	46	0.79 (0.59, 1.06)	0.79 (0.59, 1.06)	2.54	−0.33 (−0.75)	0.79 (0.62)
Metabolism and nutrition disorders	47	0.78 (0.58, 1.04)	0.78 (0.59, 1.03)	2.87	−0.35 (−0.76)	0.78 (0.62)
Injury, poisoning, and procedural complications	301	0.77 (0.69, 0.87)	0.8 (0.73, 0.88)	18.05	−0.33 (−0.5)	0.8 (0.72)
Gastrointestinal disorders	191	0.77 (0.66, 0.89)	0.78 (0.68, 0.89)	12.8	−0.36 (−0.57)	0.78 (0.69)
Congenital, familial, and genetic disorders	6	0.7 (0.31, 1.56)	0.7 (0.31, 1.56)	0.77	−0.51 (−1.58)	0.7 (0.36)
Reproductive system and breast disorders	13	0.68 (0.4, 1.18)	0.69 (0.4, 1.19)	1.88	−0.54 (−1.3)	0.69 (0.43)
Respiratory, thoracic, and mediastinal disorders	85	0.59 (0.48, 0.73)	0.6 (0.48, 0.74)	23.57	−0.73 (−1.04)	0.6 (0.5)
Renal and urinary disorders	31	0.5 (0.35, 0.72)	0.51 (0.36, 0.73)	15.09	−0.98 (−1.48)	0.51 (0.38)
Skin and subcutaneous tissue disorders	83	0.45 (0.36, 0.56)	0.46 (0.37, 0.57)	54.87	−1.11 (−1.42)	0.46 (0.39)
Hepatobiliary disorders	10	0.39 (0.21, 0.72)	0.39 (0.21, 0.73)	9.6	−1.36 (−2.21)	0.39 (0.23)
Musculoskeletal and connective tissue disorders	61	0.37 (0.29, 0.47)	0.38 (0.29, 0.49)	64.74	−1.39 (−1.75)	0.38 (0.31)
Eye disorders	21	0.35 (0.23, 0.53)	0.35 (0.23, 0.54)	25.61	−1.51 (−2.11)	0.35 (0.25)
Infections and infestations	38	0.21 (0.15, 0.28)	0.22 (0.16, 0.3)	114.26	−2.21 (−2.66)	0.22 (0.17)
Neoplasms: benign, malignant, and unspecified (including cysts and polyps)	9	0.07 (0.04, 0.13)	0.07 (0.04, 0.13)	110.81	−3.78 (−4.68)	0.07 (0.04)

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Abbreviations: ROR, Reporting Odds Ratio; PRR, Proportional Reporting Ratio; IC, Information Component; EBGM, Empirical Bayes Geometric Mean.

PT signals

The 30 most common AE signals related to solriamfetol that met the criteria of all four statistical methods (ROR, PRR, BCPNN, and MGPS) are summarized in Table 3. We coded these AEs using PTs from MedDRA® to characterize the toxicity profile of solriamfetol. The results showed that psychiatric and nervous system disorders were reported most frequently in patients treated with solriamfetol.

Table 3. The top 30 AE signals related to solriamfetol ranked by number at the PT level in the FAERS database.

Preferred Terms	N	System Organ Class	ROR (95% CI)	PRR (95% CI)	χ2 statistic	IC (IC025)	EBGM (EBGM05)
Drug ineffective	362	General disorders and administration site conditions	5.51 (4.93, 6.15)	4.96 (4.5, 5.47)	1173.83	2.31 (2.15)	4.96 (4.53)
Headache	143	Nervous system disorders	5.14 (4.35, 6.09)	4.95 (4.23, 5.79)	454.53	2.31 (2.06)	4.95 (4.3)
Anxiety	120	Psychiatric disorders	9.2 (7.67, 11.05)	8.88 (7.44, 10.59)	841.38	3.15 (2.89)	8.87 (7.61)
Blood pressure increased	56	Investigations	7.17 (5.51, 9.35)	7.06 (5.47, 9.11)	291.68	2.82 (2.44)	7.05 (5.65)
Depression	53	Psychiatric disorders	5.95 (4.54, 7.81)	5.86 (4.45, 7.71)	214.31	2.55 (2.16)	5.86 (4.67)
Suicidal ideation	46	Psychiatric disorders	13.4 (10.01, 17.94)	13.21 (9.85, 17.72)	518.86	3.72 (3.31)	13.19 (10.33)
Palpitations	39	Cardiac disorders	7.93 (5.78, 10.88)	7.84 (5.73, 10.73)	232.81	2.97 (2.52)	7.83 (6.01)
Insomnia	35	Psychiatric disorders	3.2 (2.29, 4.46)	3.17 (2.27, 4.42)	52.26	1.67 (1.19)	3.17 (2.4)
Therapeutic response decreased	35	General disorders and administration site conditions	13.27 (9.51, 18.53)	13.13 (9.41, 18.32)	391.83	3.71 (3.24)	13.11 (9.92)
Migraine	30	Nervous system disorders	6.21 (4.33, 8.9)	6.16 (4.33, 8.77)	129.63	2.62 (2.11)	6.15 (4.55)
Heart rate increased	27	Investigations	5.91 (4.05, 8.64)	5.87 (4.04, 8.52)	109.15	2.55 (2.02)	5.87 (4.27)
Feeling jittery	26	General disorders and administration site conditions	41.38 (28.09, 60.94)	41.03 (27.72, 60.72)	1009.62	5.35 (4.8)	40.79 (29.5)
Exposure during pregnancy	26	Injury, poisoning, and procedural complications	7.69 (5.23, 11.32)	7.63 (5.16, 11.29)	149.9	2.93 (2.38)	7.63 (5.52)
Hyperhidrosis	24	Skin and subcutaneous tissue disorders	4.51 (3.02, 6.75)	4.49 (3.03, 6.64)	65.11	2.17 (1.6)	4.48 (3.2)
Sleep apnoea syndrome	22	Respiratory, thoracic, and mediastinal disorders	22.44 (14.74, 34.15)	22.28 (14.76, 33.63)	445.89	4.47 (3.88)	22.21 (15.63)
Irritability	22	Psychiatric disorders	11.08 (7.28, 16.86)	11.01 (7.3, 16.62)	199.96	3.46 (2.87)	10.99 (7.74)
Drug ineffective for unapproved indication	22	General disorders and administration site conditions	6.72 (4.42, 10.23)	6.68 (4.43, 10.08)	106.28	2.74 (2.15)	6.67 (4.7)
Tachycardia	21	Cardiac disorders	5.18 (3.37, 7.95)	5.15 (3.35, 7.93)	70.22	2.36 (1.76)	5.14 (3.59)
Therapeutic response unexpected	20	General disorders and administration site conditions	10.23 (6.59, 15.88)	10.17 (6.61, 15.65)	165.18	3.34 (2.72)	10.15 (7.03)
Product administration interrupted	19	Injury, poisoning, and procedural complications	24.89 (15.84, 39.1)	24.74 (15.76, 38.83)	431.31	4.62 (3.99)	24.65 (16.89)
Therapeutic response shortened	18	General disorders and administration site conditions	7.62 (4.79, 12.11)	7.58 (4.74, 12.13)	102.71	2.92 (2.27)	7.57 (5.13)
Pre-existing condition improved	17	General disorders and administration site conditions	63.24 (39.18, 102.08)	62.89 (39.29, 100.66)	1026.13	5.96 (5.29)	62.33 (41.75)
Agitation	16	Psychiatric disorders	6.28 (3.84, 10.26)	6.25 (3.83, 10.2)	70.55	2.64 (1.95)	6.24 (4.14)
Narcolepsy	14	Nervous system disorders	164.18 (96.52, 279.26)	163.42 (96.27, 277.42)	2207.82	7.32 (6.58)	159.67 (102.37)
Dry mouth	14	Gastrointestinal disorders	4.12 (2.43, 6.96)	4.1 (2.42, 6.96)	32.86	2.04 (1.3)	4.1 (2.64)
Disturbance in attention	12	Nervous system disorders	5.19 (2.94, 9.16)	5.18 (2.93, 9.14)	40.43	2.37 (1.58)	5.17 (3.22)
Panic attack	9	Psychiatric disorders	6.11 (3.17, 11.75)	6.09 (3.19, 11.63)	38.29	2.61 (1.71)	6.09 (3.52)
Abortion spontaneous	9	Pregnancy, puerperium, and perinatal conditions	5.31 (2.76, 10.22)	5.3 (2.78, 10.12)	31.37	2.4 (1.51)	5.29 (3.06)
Anger	8	Psychiatric disorders	6.58 (3.29, 13.17)	6.56 (3.3, 13.03)	37.72	2.71 (1.77)	6.56 (3.67)
Restless legs syndrome	7	Nervous system disorders	8.6 (4.1, 18.07)	8.59 (4.08, 18.09)	46.87	3.1 (2.1)	8.58 (4.61)

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Abbreviations: ROR, Reporting Odds Ratio; PRR, Proportional Reporting Ratio; IC, Information Component; EBGM, Empirical Bayes Geometric Mean.

In particular, the most common AEs were drug ineffective (n = 362, PT: 10013709), headache (n = 143, PT: 10019211), anxiety (n = 120, PT: 10002855), blood pressure increased (n = 56, PT: 10005750), depression (n = 53, PT: 10012378), suicidal ideation (n = 46, PT: 10042458), palpitations (n = 39, PT: 10033557), and insomnia (n = 35, PT: 10022437).

To further explore indication-specific safety profiles, we performed stratified signal analyses based on the reported indications for solriamfetol use. The top AE signals for patients treated for narcolepsy are summarized in S2 Table, while those for patients treated for OSA are shown in S3 Table. While drug ineffective (149 reports in narcolepsy, 14 reports in OSA), headache (54 reports in narcolepsy, 11 reports in OSA), and anxiety (47 reports in narcolepsy, 9 reports in OSA) were the most frequently reported PT in both groups, differences emerged in specific signal strengths. In the OSA group, several AE signals showed markedly elevated RORs, including therapeutic response unexpected (ROR = 43.56), therapeutic response decreased (ROR = 20.46), and feeling jittery (ROR = 60.88). Cardiovascular-related events such as palpitations (ROR = 6.95) and headache (ROR = 4.85) also ranked high. In contrast, the narcolepsy group exhibited stronger psychiatric-related signals. Notably, suicidal ideation (ROR = 4.54), agitation (ROR = 5.72), mania (ROR = 7.20), and persecutory delusion (ROR = 32.81) were prominent.

Time to onset of solriamfetol‑related AEs

We retrieved the time to onset of solriamfetol-related AEs from the FAERS database (Fig 3). After reports with implausible or missing onset times were excluded, 77 AEs with recorded onset times were retained. The median time to onset was 7 days (interquartile range: 0–55 days). As shown in Fig 3A, a majority of the AEs (n = 36, 46.8%) were reported within 7 days following the initiation of solriamfetol treatment. In addition, the highest number of AEs occurring within 7 days of treatment initiation occurred on the day of the first administration (n = 25, 69.4%) (Fig 3B).

Discussion

Despite undergoing extensive clinical trials before being approved for commercial use, pharmaceuticals may induce severe AEs in clinical settings. Therefore, post-marketing surveillance is crucial, as it enables prompt identification and management of potential AEs [20].

This study showed notable sex disparity in reports of solriamfetol-related AEs, with 64.06% of reports involving women. These findings suggest that women are more likely to experience or report solriamfetol-related AEs, which may be attributed to physiological differences in drug metabolism between men and women or differences in patient-reported behaviors [21,22]. Among the subset of reports with available age data, the median age of patients experiencing solriamfetol-related AEs was 40 years. While this may suggest that the drug is often used by young and middle-aged adults—consistent with the age distribution of narcolepsy and OSA [23]—the results should be cautious as age data is missing for approximately 78% of cases in our data. Furthermore, the proportion of solriamfetol-related AE reports was higher in the United States (90.52%), which was expected because solriamfetol was first approved for clinical use in the United States [14]. Additionally, solriamfetol prescriptions in Europe are generally more strictly limited to approved indications (narcolepsy and OSA), whereas off-label use may be more prevalent in the United States. This difference in prescribing restrictions may also contribute to the greater number of AE reports from the United States.

Notably, there was a decline in the number of solriamfetol-related AE reports after 2022, with fewer cases recorded in 2023 and early 2024. Several factors may account for this trend. First, increased familiarity with solriamfetol by clinicians and patients may have led to improved management of expected side effects, thereby reducing the likelihood of reporting. Second, voluntary underreporting may increase over time, especially for known or anticipated AEs. However, due to the passive nature of the FAERS system, the exact reasons behind this decline remain speculative and warrant further exploration.

A total of 30 disproportionality signals were identified for solriamfetol-related AEs, including headache, anxiety, decreased appetite, and insomnia. These signals are consistent with those reported in a previous study [24]. At the SOC level, significant signals were primarily attributed to psychiatric disorders; pregnancy, puerperium, and perinatal conditions; nervous system disorders; general disorders and administration site conditions; and cardiac disorders. It should be noted that the SOC classification strictly follows MedDRA rules and does not necessarily reflect the clinical nature of the events.

General disorders and administration site conditions were the most frequently reported solriamfetol-related AEs. In our dataset, the category ‘general disorders and administration site conditions’ mainly encompassed adverse events such as drug ineffectiveness, decreased therapeutic response, feeling jittery, and unexpected therapeutic response. In particular, drug ineffectiveness was the most frequent AE. However, a retrospective study showed that 91% of patients on solriamfetol reported a slight or strong improvement in EDS and 94% of physicians found a slight or strong improvement in EDS in their patients [21]. This finding may be attributed to the oral administration of solriamfetol, as its efficacy stabilizes only after 1 week and lasts up to 12 weeks [17]. However, this study showed that a majority of solriamfetol-related AEs (46.8%) were reported within 7 days of treatment initiation and 69.4% of these AEs were reported on the first day of treatment initiation. The drug may not have reached the period of optimal efficacy at the time the AEs were reported. It is also possible that some of these early-onset AEs, occurring predominantly within the first 7 days, may be directly substance-related due to the pharmacological action of solriamfetol. However, non-specific effects such as anticipatory anxiety, placebo–nocebo responses, or adjustment reactions at treatment initiation cannot be excluded and should be considered in interpreting these results. It is also worth noting that the perception of drug ineffectiveness could be influenced by multiple factors such as subtherapeutic dosing, non-adherence, or concomitant medications. However, the FAERS database lacks some detailed and standardized data on dosing regimens, treatment duration, or co-medications, which limits our ability to analyze these influences further.

Among solriamfetol-induced nervous system disorders, headache was one of the most prominent AEs. Consistently, a pooled analysis of three studies showed that the most common adverse reaction in the solriamfetol group versus the placebo group was headache (16% versus 7%) [17,25,26]. Solriamfetol is a dual norepinephrine and dopamine reuptake inhibitor that prevents the resorption of the two neurotransmitters and increases their concentrations in the brain [10]. This inhibition can activate the sympathetic nervous system, leading to vasoconstriction, which may trigger headaches. As a stimulant, solriamfetol promotes wakefulness. Heightened stimulation by solriamfetol may activate pain receptors in the brain, leading to headaches. A similar mechanism is observed for other central nervous system stimulants, such as caffeine, which are known to cause headaches in some individuals [27].

Among solriamfetol-induced psychiatric disorders, anxiety, depression, suicidal ideation, insomnia, irritability, agitation, panic attacks, and anger were more common AEs. Owing to the inhibition of neurotransmitter reuptake, the concentration of neurotransmitters increases in the synaptic gap. This increase in the levels of neurotransmitters promotes wakefulness and concentration while potentially triggering excessive nervous system arousal, which can lead to mental abnormalities such as anxiety, agitation, and nervousness. Abnormalities in the nervous system typically lead to severe AEs. In a study investigating the long-term safety of solriamfetol, approximately 10% of patients discontinued treatment owing to severe AEs and the most common AEs leading to discontinuation were psychiatric disorders [28]. When participants with a history of psychiatric disorders were excluded, no AE signals indicative of psychiatric disorders were detected [29]. These findings emphasize that a detailed psychiatric and medical history assessment is necessary before prescribing solriamfetol. Treatment may be initiated with the lowest effective dose of solriamfetol, and the dose should be increased gradually to minimize the risk of psychiatric side effects.

Among solriamfetol-induced cardiac disorders, palpitations and tachycardia were the most common AEs. By increasing norepinephrine and dopamine levels, solriamfetol stimulates the sympathetic nervous system, leading to enhanced cardiovascular responses such as an increased heart rate and contractility. This state of sympathetic arousal can manifest as palpitations and increased blood pressure [30]. In the EU, solriamfetol is contraindicated in patients with recent myocardial infarction, serious arrhythmias, or other severe cardiac conditions [31]. In the United States, solriamfetol is not recommended for patients with unstable or severe cardiovascular disease; however, contraindication is not deemed mandatory [32]. Altogether, clinicians should assess the heart rate and blood pressure of patients before initiating treatment with solriamfetol and periodically during treatment to obtain better insights into the safety of the drug.

With regard to the effects of solriamfetol on pregnant women, 9 cases of spontaneous abortion were reported. This is of particular concern, especially for women of childbearing potential. In the EU, solriamfetol is not recommended during pregnancy [31]. However, in the United States, evidence regarding the occurrence of solriamfetol-related AEs in pregnant women is inadequate [32]. Given the potential severity of this adverse event, solriamfetol should be prescribed to women of reproductive age only after careful risk–benefit evaluation. Pregnancy prevention strategies should be discussed and implemented where appropriate.

When comparing our findings with the approved U.S. prescribing information for solriamfetol, several newly detected AEs emerged from the FAERS database that are not prominently highlighted in the official labeling. Specifically, unexpected therapeutic response, shortened therapeutic response, irritability, agitation, and suicidal ideation showed statistically significant signals across all four disproportionality algorithms. While common AEs such as headache, anxiety, nausea, and insomnia are consistent with those listed in the prescribing information, the identification of psychiatric symptoms like persecutory delusion and mania—particularly among narcolepsy patients—suggests the need for heightened clinical awareness. Moreover, cardiovascular-related events such as palpitations and increased blood pressure also demonstrated elevated signal strength, especially in the OSA group, and warrant further prospective evaluation. These findings underscore the added value of post-marketing surveillance in detecting rare or unexpected AEs that may not have been captured during pre-approval trials.

The FAERS database contains sufficient reports to identify rare adverse reactions that are difficult to detect through traditional epidemiological methods. However, it has several inherent limitations. First, as a global spontaneous reporting system, the FAERS database is subject to inherent selection biases, including incomplete documentation of reported cases. Additionally, as voluntary reporting allows consumers to submit AE reports, the professionalism of some reports may be compromised. Second, controversy may arise regarding certain AEs because the FDA does not mandate evidence of causation. Consequently, we could not establish a causal relationship between solriamfetol and the reported AEs. Third, the FAERS database lacks comprehensive information; therefore, confounding factors such as age, comorbidities, and other variables were not controlled for in this study. Fourth, owing to the limitations of the FAERS database, we did not conduct correlation analysis on data collected from the same locations or countries, which might have introduced bias. Fifth, most AEs were reported in patients with narcolepsy, a population in which polypharmacy is common due to the complex symptomatology and need for combination treatment. However, the FAERS database does not consistently provide data on co-administered medications, which limits our ability to account for confounding factors. Despite the significant limitations of the FAERS database for pharmacovigilance studies, we identified and analyzed AE signals related to solriamfetol that may guide future clinical studies. Altogether, the ongoing monitoring of the efficacy and safety of solriamfetol remains critical.

Conclusion

In conclusion, our analysis of FAERS data provides real-world pharmacovigilance insights into the adverse event profile of solriamfetol. The most frequently reported side effects—including headache, anxiety, and insomnia—are consistent with those observed in prior clinical trials. However, due to the limitations inherent to spontaneous reporting systems, including potential bias, incomplete data, and lack of causality confirmation, these findings should be interpreted with caution. Further prospective studies are warranted to validate these associations.

Supporting information

S1 Table. Four major algorithms used for signal detection.

(DOCX)

pone.0333130.s001.docx^{(17.5KB, docx)}

S2 Table. Signal Strength of Adverse Events Associated with Solriamfetol for the Treatment of Narcolepsy: Ranked by Number of Reports at the PT Level in the FAERS Database.

(DOCX)

pone.0333130.s002.docx^{(21KB, docx)}

S3 Table. Signal Strength of Adverse Events Associated with Solriamfetol for the Treatment of Obstructive Sleep Apnea: Ranked by Number of Reports at the PT Level in the FAERS Database.

(DOCX)

pone.0333130.s003.docx^{(18.4KB, docx)}

Acknowledgments

We thank Bullet Edits Limited for the linguistic editing and proofreading of the manuscript.

Abbreviations

AEs: adverse events
FAERS: Food and Drug Association Adverse Event Reporting System
FDA: Food and Drug Administration
PTs: preferred terms
SOCs: Social Organ Classes

Data Availability

The dataset supporting the conclusions of this article is available through the public FDA Adverse Event Reporting System database at https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.

Funding Statement

This work is financially supported by grants from the Jiangsu Pharmaceutical Association (Grant No. H202311).

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PLoS One. doi: 10.1371/journal.pone.0333130.r001

Decision Letter 0

Christian Veauthier

6 May 2025

PONE-D-25-14184Post-marketing Safety of Solriamfetol: A Retrospective Pharmacovigilance Study Based on the US Food and Drug Administration Adverse Event Reporting System

PLOS ONE

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Reviewer #1: The study analizes AEs of solriamfetol retrospectively using real-world data.

P4 line 55: Authors should clearly state if they refer to EDS in general, in narcolepsy or in OSA. Otherwise the mentioning of specific wake promoting agents does not make sense, since they are approved for certain indications only. Pitolisant as alternative has not been mentioned.

Table 1: it should be mentioned that the prescription in Europe is much more restricted to the approved indications as in the US, which could attribute to the high amount of AEs in the US.

Table 2 needs a legend of abbreviations. The AEs are rather unspecfic. There seems to be much more information about different psychiatric disorders and cardiac symptoms as can be seen in table 3. Could drug ineffectiveness be dependant on dosage or comedication? There is no information about this. Therefore it would be nice to have some more information about the settings of the FAERS database.

What are general disorders, please explain in more detail.

What do you consider to be poisoning? Is this term directly related to intake of solriamfetol only or is it including all preexisting forms of medication, alcohol and drug abuse etc.?

I suggest to give table 3 a better structure by listing all psychiatric disorders first according to frequency followed by nervous system disorders etc.

P19 line 163: Since most AEs were reported within the first 7 days it would be good to discuss if these were in fact substance related or unspecific. Moreover the most important AE for women would be spontaneous abortion. This needs special consideration, because it would imply not to prescribe solriamfetol for women with child bearing potential.

Given all the limitation of the FAERS database at the end of the discussion, the conclusion should be much more cautious. It should mention that the most common side effets of the initial solriamfetol studies were confirmed. I suggest to mention the study limitations clearly in the method chapter to shed a light on the presented results, instead of presenting them at the very end.

The discussion should certainly comment the decline of AEs from 2023 on.

Reviewer #2: The paper by Wu and Zhu describes the frequency of AEs due to Solriamfetol treatment. They used the FEARS database for analysis.

The paper is overall well structured and written.

The paper has many limitations and severe concerns that need to be addressed:

1.- Funding: Please elaborate further on the funding of this project. I could not find any additional information on the Grant No. H202311.

2.- Abstract: “EDS…and may be life-threatening”. This is true in the context of car accident etc., but the wording here is a little unfortunate. Please rephrase this sentence.

3.- Introduction: For a better description of what is EDS you should consider Lammers et al., Sleep Med Rev, 2020.

4.- Introduction: I disagree with your statement “Although continuous positive airway pressure is effective, EDS may persist in patients with OSA, almost all of whom undergo pharmacological therapy [8]”. Please provide data on this statement. I´m not aware of such data. Only some patients undergo pharmacological therapy, not “almost all”.

5.- Introduction: Next, you describe “Modafinil and armodafinil promote arousal and are currently used as first-line treatments for EDS in adults”. The reference you provide does not refer to EDS in OSA or in narcolepsy. You´re not precise here and are mixing up different things. Please clarify in the introduction what are current pharmacological recommendations for EDS in narcolepsy, for EDS in OSA and for other, if available.

6.- Methods/ Discussion/ Conclusions: Limitation of FEARS database: It includes data from “various sources, including medical professionals, consumers,…”. And as described in the results, mostly consumers (>50%) reported AEs. The FEARS database itself describes all its limitations on their webpage. You mention most, but not all of them. Further, for a lot of data “unknown” or “other” is described. I.e. you cannot make strong statement on age “median age was 40”, if 78% of data on age are “unknown”. This also refers to other points in your discussion.

7.- The discussion is too long and repeats results.

8.- Conclusion: I disagree with your conclusion. It is very worrying that, despite the very limited data available and all the serious limitations, you end up concluding that “serious AEs” occur with solriamfetol. The side effects mentioned generally correspond to the known side effects and no real statement can be made about the frequency due to the given limitations. What are the serious AEs?

9.- Most AEs are reported in the context of treatment for narcolepsy. This is not mentioned or discussed. Many patients with narcolepsy receive co- medication or polypharmacy. Another limitation, which is not mentioned.

10.- As further recommendation: In my opinion, it would be interesting if you could split the data sets into a part with results from consumer reports and a part with reports from physicians and compare results.

Reviewer #3: This paper summarizes the postmarketing reports of adverse effects of solriamfetol. The methodology and statistical analysis is sound, the manuscript is written well and the discussion is appropriate, addressing the relevant imitations of such methodology.

The only point I am curious about is the details of serious adverse effects such as hospitalization and death. If possible, it would be very enlightening to add the details regarding these serious AEs, like why the patients were hospitalized or left disabled etc.

Other than that, I have no further comments. It was a pleasure to review this paper.

Thank you.

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Reviewer #1: Yes: Geert Mayer

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Reviewer #3: No

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PLoS One. 2025 Sep 22;20(9):e0333130. doi: 10.1371/journal.pone.0333130.r002

Author response to Decision Letter 1

5 Jun 2025

We revised the article and responded to the reviewer in the responses letter, thank you for your help

Attachment

Submitted filename: Response to Reviewers.docx

pone.0333130.s005.docx^{(33.3KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0333130.r003

Decision Letter 1

Christian Veauthier

1 Jul 2025

PONE-D-25-14184R1Post-marketing Safety of Solriamfetol: A Retrospective Pharmacovigilance Study Based on the US Food and Drug Administration Adverse Event Reporting SystemPLOS ONE

Dear Dr. Zhu,

You have addressed the critical comments of the experts; unfortunately, methodological and substantive weaknesses continued to emerge during the review, which I would like to explain:

On the one hand, some reviewers criticized the fact that the data are not new and does not add any significant information to the data already published, but this is not a criterion for publication in Plos One.

Secondly, and more important, after inviting additional reviewers, there are also points of content that make publication in the current version impossible. The basic problem here seems to be that You are writing an article about a molecule (Solriamfetol) and not about a therapy for a distinct disorder. The situation would be completely different if the side effects of treating narcolepsy patients with Solriamfetol had been evaluated – or OSA patients with Solriamfetol…. But different indications are being lumped together here. Moreover, there seem to be also patients without narcolepsy or OSA? And there is little information about comorbidities. But the effects can only be meaningfully assessed if the indication and comorbidities are also known. Otherwise, this should have to be described as a serious methodological limitation (e.g. how many patients with elevated blood pressure already had elevated blood pressure before or were taking antihypertensives? Did this only occur in sleep apnea patients or also in narcolepsy patients?).

Therefore, before publication in Plos One, a fundamental major revision of the article would be necessary, highlighting the methodological shortcomings mentioned, and we cannot guarantee that the article will be accepted next time. In addition, I also refer to further comments from the reviewers.

==============================

Please submit your revised manuscript by Aug 15 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Christian Veauthier, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments:

You have addressed the critical comments of the experts; unfortunately, methodological and substantive weaknesses continued to emerge during the review, which I would like to explain:

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

Reviewer #4: All comments have been addressed

Reviewer #5: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Partly

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

6. Review Comments to the Author

Reviewer #1: The paper has improved in clarity by responding in depth to all the reviewers comments. However the "real wolrd data" presented through the FAERS data analysis does not really add anything new to the knowlege about solriamfetol

Reviewer #3: I have no further comments. I believe, within the constraints of the methodology and dataset employed, this is the most that can be reasonably achieved.

Thank you.

Reviewer #4: (No Response)

Reviewer #5: As a clinician, I find it difficult to know exactly what to do with the data presented. Who is reporting in the FAERS and why? It is also not clear how this report on solriamfetol compares with reports on other similar drugs or drugs for similar indications.

For me, it is also not entirely clear from the current description exactly what kind of statistics were applied and how to fully understand them. But that is not crucial for the more general discussion of what to do with data from databases like this.

Apparently, most reports are from people who do not use solriamfetol for narcolepsy or OSAS. It then makes an addition, which is difficult for me to understand, that ‘the most frequently reported indication for solriamfetol was narcolepsy (596, 38.45%), followed by OSA (57, 3.68%)’. All other indications thus constitute < 3.68% of the total group. This implies that at least 15 other indications for solriamfetol were reported! Moreover, if I understand it correctly, the most often reported is that the drug is not effective. Personally, I would not interpret that as an AE.

Finally, methodological issues aside, what is reported on AEs is not really new or unexpected.

Nevertheless, the previous reviewer comments have been adequately addressed.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy .

Reviewer #1: No

Reviewer #3: No

Reviewer #4: Yes: Markku Partinen

Reviewer #5: No

**********

PLoS One. 2025 Sep 22;20(9):e0333130. doi: 10.1371/journal.pone.0333130.r004

Author response to Decision Letter 2

31 Jul 2025

As a clinician, I find it difficult to know exactly what to do with the data presented. Who is reporting in the FAERS and why? It is also not clear how this report on solriamfetol compares with reports on other similar drugs or drugs for similar indications.

Response: We sincerely thank the reviewer for raising this important point. The primary objective of our study is to identify the most frequently reported AEs associated with solriamfetol based on data from the FAERS database. While we fully acknowledge that causality cannot be established from spontaneous reports, such analyses are widely used in pharmacovigilance to generate early safety signals and provide real-world insights that can inform clinical monitoring and future research.

Regarding the question of "who is reporting and why," we have clarified this in both the Methods section and Table 1, which provides reporter types. The majority of AE reports were submitted by healthcare professionals and consumers. We have now further emphasized this in the revised manuscript to improve clarity.

As for comparisons with other drugs used for similar indications (e.g., modafinil, pitolisant), we recognize the value of such analyses; however, our study was specifically designed to focus on solriamfetol and to explore its safety profile across all reported indications. Comparative analyses have been addressed in prior publications, and we consider them beyond the scope of the current investigation. We also have a brief summary in this article .

Response: We appreciate the reviewer’s comment regarding the statistical methods used. In this study, we employed four widely accepted disproportionality analysis algorithms: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS).

Each method offers distinct advantages:

– ROR is effective in correcting biases that may arise from low event counts.

– PRR provides higher specificity in detecting safety signals.

– BCPNN excels in integrating multi-source data and performing cross-validation.

– MGPS is particularly useful for identifying rare adverse events.

By combining these four methods, we aimed to enhance signal detection robustness and reliability. The joint use of multiple algorithms allows for cross-validation, helping to reduce false positives and increase the credibility of the findings. This strategy also broadens the detection scope and allows for the identification of potential rare adverse reactions through threshold adjustments and variance control.

Response: In response to the major concern regarding the heterogeneity of indications and lack of indication-specific analysis, we have added two new supplementary tables:

� STable 2: Signal strength of adverse events associated with solriamfetol for the treatment of narcolepsy.

� STable 3: Signal strength of adverse events associated with solriamfetol for the treatment of obstructive sleep apnea (OSA).

These tables allow for a clearer understanding of the safety profile of solriamfetol across its approved indications. The results show that while certain adverse events (e.g., drug ineffectiveness, headache, anxiety) are common to both indications, there are distinct signal differences in severity and ranking. We added a description of the corresponding content in the results section.

For reported indications. As shown in Table 1, we clearly listed the proportions of the two approved indications—narcolepsy (38.45%) and obstructive sleep apnea (3.68%)—in the included reports. However, 58.19% of the reports lacked specific indication information. This high percentage does not necessarily imply other indications. Rather, it reflects missing or incomplete data within the FAERS database, a common limitation in spontaneous reporting systems.

We agree that “drug ineffective” may not represent a physiological adverse event in the traditional sense. However, in pharmacovigilance practice, especially within spontaneous reporting systems like FAERS, “drug ineffective” is a commonly reported Preferred Term (PT) that reflects real-world dissatisfaction with therapeutic outcomes. While it does not necessarily indicate harm, a high frequency of such reports can serve as an important early signal for suboptimal drug response, inappropriate patient selection, dosing issues, or emerging patterns of therapeutic failure. Regulatory agencies such as the FDA consider these signals valuable for post-marketing surveillance and risk-benefit assessment.

Finally, methodological issues aside, what is reported on AEs is not really new or unexpected.

Response: We thank the reviewer for this important observation. In response to this concern, we have added a new paragraph to the Discussion section comparing the adverse events (AEs) identified in our study with those listed in the official U.S. prescribing information for solriamfetol (Sunosi®). While several commonly reported AEs such as headache, anxiety, and insomnia are consistent with the product labeling, we also identified a number of previously underreported or unlabeled AEs—including therapeutic response decreased, irritability, suicidal ideation, mania, and persecutory delusion—which showed statistically significant signals in our FAERS analysis.

Importantly, through indication-specific stratified analysis, we found that psychiatric-related AEs were disproportionately reported in patients with narcolepsy, whereas cardiovascular-related AEs were more prominent in patients with OSA. These findings go beyond the current labeling and highlight indication-specific safety concerns that may not have been captured in pre-marketing clinical trials. We believe this adds novel, clinically relevant insights and underscores the value of post-marketing pharmacovigilance in complementing existing drug safety information.

We hope that these major revisions sufficiently address the methodological and interpretational concerns raised and bring the manuscript in line with the standards of PLOS ONE.

Thanks for your attention to our manuscript!

Sincerely,

Kaijian Zhu

Email: 13515245847@163.com

Attachment

Submitted filename: Response to Reviewers-2.docx

pone.0333130.s006.docx^{(28.8KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0333130.r005

Decision Letter 2

Christian Veauthier

19 Aug 2025

<div>PONE-D-25-14184R2Post-marketing Safety of Solriamfetol: A Retrospective Pharmacovigilance Study Based on the US Food and Drug Administration Adverse Event Reporting SystemPLOS ONE

Dear Dr. Zhu,

The first column of Table 2 is labeled “Preferred Terms” and the second column is labeled “System Organ Class”. There seam to be obvious errors here: e.g., the organ “Renal and urinary disorders” is mentioned for the preferred term “cataplexy”. What does cataplexy have to do with renal and urinary disorders?

Or Sleep attacks with neoplasms? On the other hand, some information is incomprehensible: for example, why does “Suicidal intention” is mentionned under "investigations"? Readers cannot understand this without a comment in the legend.

The entire Table 2 appears to be full of errors. Please read carefully before resubmission all tables and ensure that the tables are error-free.

Please submit your revised manuscript by Oct 03 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Christian Veauthier, M.D.

Academic Editor

PLOS ONE

Journal Requirements:

1. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

2. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #3: All comments have been addressed

Reviewer #5: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #3: Yes

Reviewer #5: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: Yes

Reviewer #5: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #3: Yes

Reviewer #5: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #3: Yes

Reviewer #5: Yes

**********

6. Review Comments to the Author

Reviewer #3: Although this study inherently suffers from the limitations of utilizing FAERS as the data source, I do not think any additional revisions could improve the manuscript at this point. I do not have any further comments.

Reviewer #5: The previous comments have been properly addressed.

But, something went wrong in Table S2: the second column is not correctly matched to the first column. Whether there is possibly also an error in the other columns I cannot determine.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy .

Reviewer #3: No

Reviewer #5: No

**********

PLoS One. 2025 Sep 22;20(9):e0333130. doi: 10.1371/journal.pone.0333130.r006

Author response to Decision Letter 3

22 Aug 2025

22-Agu-2025

Dear Prof. Christian Veauthier,

Thank you for your time and valuable feedback on our manuscript entitled "Post-marketing Safety of Solriamfetol: A Retrospective Pharmacovigilance Study Based on the US Food and Drug Administration Adverse Event Reporting System" (Submission ID PONE-D-25-14184R2). We have carefully addressed all comments and suggestions. Modifications in the revised manuscript are highlighted in red, and point-by-point responses are provided below:

Additional Editor Comments:

The manuscript is significantly better and should be published soon, but there are still errors in Table 2:

The entire Table 2 appears to be full of errors. Please read carefully before resubmission all tables and ensure that the tables are error-free.

Reviewer: 5

Comment 1

The previous comments have been properly addressed.

But, something went wrong in Table S2: the second column is not correctly matched to the first column. Whether there is possibly also an error in the other columns I cannot determine.

Response to Editor and Reviewer #5:

Thank you for your valuable feedback. We have carefully reviewed your comments and thoroughly re-examined the manuscript. Upon our careful recheck, we found that the issue was primarily confined to Table S2, where there was a misalignment between the "Preferred Terms" and the "System Organ Classes." This error was due to incorrect matching during the table preparation process, which led to the confusion, such as the association of "cataplexy" with "renal and urinary disorders" and "sleep attacks" with "neoplasms."

We have corrected the entries in Table S2 to ensure that the "Preferred Terms" are properly aligned with their corresponding "System Organ Classes." After reviewing the rest of the tables, we found no similar issues.

We believe these revisions have significantly improved the accuracy of the tables, and we have attached the revised manuscript with all necessary corrections. We hope these adjustments meet your expectations.

Thanks for your attention to our manuscript!

Sincerely,

Kaijian Zhu

Email: 13515245847@163.com

Attachment

Submitted filename: Response to Reviewers-3.docx

pone.0333130.s007.docx^{(24.4KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0333130.r007

Decision Letter 3

Christian Veauthier

3 Sep 2025

PONE-D-25-14184R3Post-marketing Safety of Solriamfetol: A Retrospective Pharmacovigilance Study Based on the US Food and Drug Administration Adverse Event Reporting SystemPLOS ONE

Dear Dr. Zhu,

Unfortunately, I have one more comment to make:

in Table 2, the preferred term “sleepiness” is assigned to system class “psychiatric disorder.”

I find this difficult to understand given that the article is about narcolepsy and daytime sleepiness,

and it reveals that the authors have no concept of daytime sleepiness and think that sleepiness is psychologically induced. That is not correct: Sleep apnea can cause sleepiness. Narcolepsy can cause sleepiness as well: neither is a psychiatric disorder. Sleepiness per se is not psychiatric. Please change the organ class.

Please submit your revised manuscript by Oct 18 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Christian Veauthier, M.D.

Academic Editor

PLOS ONE

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

PLoS One. 2025 Sep 22;20(9):e0333130. doi: 10.1371/journal.pone.0333130.r008

Author response to Decision Letter 4

7 Sep 2025

7-Sep-2025

Dear Prof. Christian Veauthier,

Thank you for your time and valuable feedback on our manuscript entitled "Post-marketing Safety of Solriamfetol: A Retrospective Pharmacovigilance Study Based on the US Food and Drug Administration Adverse Event Reporting System" (Submission ID PONE-D-25-14184R3). We have carefully addressed all comments and suggestions. Modifications in the revised manuscript are highlighted in red, and point-by-point responses are provided below:

Editor Comments:

Unfortunately, I have one more comment to make:

in Table 2, the preferred term “sleepiness” is assigned to system class “psychiatric disorder.”

I find this difficult to understand given that the article is about narcolepsy and daytime sleepiness,

Response: We sincerely thank the editor for pointing out this important issue. We fully agree that sleepiness is not a psychiatric disorder, and conditions such as narcolepsy or obstructive sleep apnea can lead to excessive sleepiness through non-psychiatric mechanisms. I will now provide a detailed explanation.

We carefully reviewed our data and would like to clarify that in our Table 2, only the SOCs are presented, and the Preferred Term “sleepiness” does not actually appear in our tables. All adverse events were coded strictly according to the standardized MedDRA dictionary, which automatically maps PT to predefined SOCs. In MedDRA, some terms related to excessive daytime sleepiness (e.g., sleep attacks) may be automatically classified under the SOC “psychiatric disorders,” even though clinically these events are primarily neurological or sleep–wake phenomena rather than psychiatric in nature. This point has already been introduced in the Methods section. Therefore, the classification reflects the MedDRA structure rather than our interpretation.

In our analysis, we first presented the results at the SOC level to give a global overview of the organ systems most frequently involved. However, as the editor correctly pointed out, the SOC classification is based on MedDRA conventions and may sometimes group sleep-related events (e.g., sleep attacks) under “psychiatric disorders,” even though clinically they are not psychiatric in nature. To address this limitation and provide readers with a more accurate understanding, we also performed a PT–level analysis and explicitly listed the PTs together with their assigned SOCs in MedDRA structure. By doing so, readers can clearly see the specific events that contributed to each SOC signal and avoid misinterpreting sleep-related symptoms as psychiatric disorders.

In the revised manuscript, we have added clarifications in the Discussion to emphasize that SOC assignment follows MedDRA rules, while the PT-level analysis allows a more nuanced interpretation in line with clinical reality. We believe this approach enhances transparency and directly addresses the editor’s concern.

We sincerely thank the editor again for highlighting this important issue, which has helped us improve the clarity and rigor of our manuscript.

Thanks for your attention to our manuscript!

Sincerely,

Kaijian Zhu

Email: 13515245847@163.com

Attachment

Submitted filename: Response to Reviewers-4.docx

pone.0333130.s008.docx^{(25KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0333130.r009

Decision Letter 4

Christian Veauthier

10 Sep 2025

Post-marketing Safety of Solriamfetol: A Retrospective Pharmacovigilance Study Based on the US Food and Drug Administration Adverse Event Reporting System

PONE-D-25-14184R4

Dear Dr. Zhu,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support .

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Kind regards,

Christian Veauthier, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0333130.r010

Acceptance letter

Christian Veauthier

PONE-D-25-14184R4

PLOS ONE

Dear Dr. Zhu,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

* All references, tables, and figures are properly cited

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You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps.

Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

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on behalf of

Dr. Christian Veauthier

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. Four major algorithms used for signal detection.

(DOCX)

pone.0333130.s001.docx^{(17.5KB, docx)}

S2 Table. Signal Strength of Adverse Events Associated with Solriamfetol for the Treatment of Narcolepsy: Ranked by Number of Reports at the PT Level in the FAERS Database.

(DOCX)

pone.0333130.s002.docx^{(21KB, docx)}

S3 Table. Signal Strength of Adverse Events Associated with Solriamfetol for the Treatment of Obstructive Sleep Apnea: Ranked by Number of Reports at the PT Level in the FAERS Database.

(DOCX)

pone.0333130.s003.docx^{(18.4KB, docx)}

Attachment

Submitted filename: Response to Reviewers.docx

pone.0333130.s005.docx^{(33.3KB, docx)}

Attachment

Submitted filename: Response to Reviewers-2.docx

pone.0333130.s006.docx^{(28.8KB, docx)}

Attachment

Submitted filename: Response to Reviewers-3.docx

pone.0333130.s007.docx^{(24.4KB, docx)}

Attachment

Submitted filename: Response to Reviewers-4.docx

pone.0333130.s008.docx^{(25KB, docx)}

Data Availability Statement

The dataset supporting the conclusions of this article is available through the public FDA Adverse Event Reporting System database at https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.

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Post-marketing safety of solriamfetol: A retrospective pharmacovigilance study based on the us food and drug administration adverse event reporting system

Lingling Wu

Kaijian Zhu

Roles

Abstract

Purpose

Methods

Results

Conclusions

Introduction

Materials and methods

Data sources and mining

Fig 1. A flowchart of the participant selection process.

Statistical analysis and signal detection

Results

Descriptive analysis

Fig 2. Number of reported AEs varies by year.

Table 1. Basic information of solriamfetol-related AE reports retrieved from the FAERS database (from third quarter of 2019 to the first quarter of 2024).

SOC signals

Table 2. Signal strengths of solriamfetol-related AEs at the SOC level in the FAERS database.

PT signals

Table 3. The top 30 AE signals related to solriamfetol ranked by number at the PT level in the FAERS database.

Time to onset of solriamfetol‑related AEs

Fig 3. Time to onset of reported AEs.

Discussion

Conclusion

Supporting information

Acknowledgments

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Christian Veauthier

Roles

Author response to Decision Letter 1

Decision Letter 1

Christian Veauthier

Roles

Author response to Decision Letter 2

Decision Letter 2

Christian Veauthier

Roles

Author response to Decision Letter 3

Decision Letter 3

Christian Veauthier

Roles

Author response to Decision Letter 4

Decision Letter 4

Christian Veauthier

Roles

Acceptance letter

Christian Veauthier

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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