Disproportionality analysis of methylphenidate-associated adverse events in pediatric patients using the FDA Adverse Event Reporting System: overall signals and stratification by gender and dosage form

Methylphenidate is widely prescribed for the clinical management of pediatric patients with attention-deficit/hyperactivity disorder (ADHD), yet its safety profile remains a subject of ongoing concern. This study aims to characterize the real-world safety profile of methylphenidate in children and adolescents using the FDA Adverse Event Reporting System (FAERS) database.

Adverse drug event (ADE) reports for individuals aged 6-17 years were extracted from the FAERS database via OpenVigil 2.1. Disproportionality analyses were performed to detect methylphenidate-associated safety signals, including overall signal detection as well as subgroup analyses stratified by gender and dosage form.

From 8,585 reports, methylphenidate-associated adverse drug reaction (ADR) signals involved 16 System Organ Classes (SOCs), most frequently psychiatric disorders; general disorders and administration site conditions; and nervous system disorders. Several potential signals not listed in current drug labels were identified, including abnormal behavior, disturbance in social behavior, and coronary artery dissection. Gender-specific analyses revealed 86 positive signals in males and 90 in females, with 41 male-exclusive and 45 female-exclusive signals. Male-exclusive signals included arrhythmia, coronary artery dissection, and acute myocardial infarction. Female-exclusive signals included tachycardia and application site reactions. Among positive signals detected in both genders, female patients showed higher reporting of application site erythema, agitation, application site pruritus, precocious puberty, and application site discolouration, whereas male patients showed higher reporting of aggression, tics, and growth retardation. Dosage-form-specific analyses showed that the immediate-release formulation was associated with acute, severe signals (e.g., sudden death, syncope). The oral extended-release formulation accounted for the largest number of unique signals (n = 63) in this dataset, although this should be interpreted with caution given differences in reporting volume across formulations. The transdermal patch was predominantly associated with application site reactions (e.g., erythema, pruritus).

This study identified overall, gender-, and dosage-form-specific ADR signals for methylphenidate in pediatric patients, including signals not currently listed in drug labels. Distinct ADR signal profiles were observed across gender and dosage-form strata. Individualized pharmacovigilance strategies may be informed by these subgroup-specific ADR signal profiles. These findings contribute to the current understanding of methylphenidate-associated ADE in children and adolescents and warrant further validation in future studies.