Isotretinoin-related adverse sexual and reproductive outcomes: a real-world pharmacovigilance study of the FDA Adverse Event Reporting System (FAERS)

BACKGROUND: Systemic isotretinoin remains the most effective therapy for severe acne and is increasingly prescribed off-label for milder disease and other sebaceous disorders such as rosacea, seborrhea, folliculitis decalvans, and hidradenitis suppurativa. While its mucocutaneous and metabolic adverse events (AEs) are well known, potential sexual and reproductive effects remain underexplored. OBJECTIVES: To evaluate isotretinoin-associated reproductive and sexual AEs using FAERS data and identify potential safety signals. METHODS: Isotretinoin-related AEs were retrieved from the FAERS Public Dashboard and OpenVigil 2.1 between January 1, 2004, and December 31, 2024. OpenVigil enables structured data extraction and applies automated preprocessing, including deduplication of identical reports. Disproportionality analyses (Proportional Reporting Ratio [PRR], Reporting Odds Ratio [ROR], and 95% confidence intervals) were performed to evaluate potential safety signals, assessing whether specific adverse events were reported more frequently with isotretinoin than with other drugs in the database. Four MedDRA® System Organ Classes were searched: Reproductive system and breast disorders, Psychiatric disorders, Investigations, and Skin and subcutaneous tissue disorders. AEs with <3 reports were excluded. In total, 92 Preferred Terms (PTs) and 1300 cases were included. Disproportionality analysis (PRR, ROR, 95% CIs) was conducted on 1151 reports where isotretinoin was the primary suspect. Statistical significance was determined using Evans' criteria. RESULTS: Between 2004 and 2024, 53,017 isotretinoin-related reports were submitted to FAERS. Among these, 1300 reproductive and sexual AEs met inclusion criteria. Most reports involved females (59.7%) and individuals aged 18-64 years (58.3%). Disproportionality analysis identified 34 AEs with statistically significant signals. 'Erectile dysfunction', 'decreased libido', and 'loss of libido' were the top three most frequently reported AEs with significant disproportionality signals (Erectile dysfunction: PRR = 4.47 [95% CI 3.88-5.14], ROR = 4.49 [95% CI 3.90-5.17]; Decreased libido: PRR = 3.63 [95% CI 2.89-4.54], ROR = 3.63 [95% CI 2.90-4.55]; Loss of libido: PRR = 4.56 [95% CI 3.57-5.84], ROR = 4.57 [95% CI 3.57-5.85]) with 195, 76, and 64 reports, respectively. Other AEs meeting significance criteria included: 'ovarian cyst', 'sexual dysfunction', 'vulvovaginal dryness', 'infertility', 'endometriosis', 'polycystic ovaries', 'female genital tract fistula', 'genital hypoaesthesia', 'dyspareunia', 'hirsutism', 'cervical dysplasia', 'testicular pain', 'penis disorder', 'anorgasmia', 'prostatitis', 'ovarian cyst ruptured', 'male sexual dysfunction', 'genital anaesthesia', 'premenstrual syndrome', 'perineal fistula', 'penile haemorrhage', 'vaginal disorder', 'varicocele', 'orgasmic sensation decreased', 'vulval disorder', 'testicular torsion', 'vulvovaginal ulceration', 'organic erectile dysfunction', 'spermatozoa abnormal', 'reproductive tract disorder', and 'genital lesion'. CONCLUSIONS: Despite inherent FAERS limitations, including underreporting, reporting bias, and lack of causal inference, our findings underscore the need to monitor sexual and reproductive side effects during isotretinoin therapy. Since such symptoms are often underreported, routine inquiry and patient education are essential to ensure safe and informed use.