Tiopronin Safety in Cystinuria: First Real-World Pharmacovigilance Analysis Using the FDA Adverse Event Reporting System (FAERS): An EAU YAU and Endourology Sections Review – Beyond the Abstract

Cystinuria is a lifelong hereditary disorder that begins in childhood and leads to recurrent cystine stone formation with a substantial risk of progressive renal damage. When conservative measures fail, tiopronin is regarded as the most effective agent for reducing urinary cystine levels.1 Despite its importance, real-world safety data for tiopronin have been limited, and most available information comes from small patient series or older reports.

In our FAERS analysis from 2014 to 2025, we identified 1,838 unique tiopronin-related cases, and nearly 70% involved pediatric patients. This reflects the early onset of cystinuria and the central role of tiopronin in managing children with this condition. Using four complementary disproportionality algorithms, we observed expected adverse events such as rash, gastrointestinal intolerance, and proteinuria, which align with established clinical experience.2,3 Several findings, however, did not appear in the current product information. Signals such as hyposmia, hypogeusia, breath odour, skin atrophy, abnormal skin texture, and tongue discolouration suggest that additional sensory and dermatologic effects may occur in routine practice.

A particularly striking observation was the strong signal for incorrect dosage administered, which appeared predominantly in children. This finding is supported by our earlier study showing that treatment compliance in cystinuria is often suboptimal, with many patients unable to maintain recommended urinary targets despite follow-up.4 Weight-based dosing, formulation limitations, caregiver experience, and the demands of lifelong therapy likely contribute to these challenges.

Real-world management issues go beyond safety signals. In many regions, including Europe, access to tiopronin remains difficult, or it is not routinely available. This creates disparities in medical management for a condition that affects children disproportionately and requires early, consistent, and long-term therapy. Limited availability combined with dosing complexity may further complicate disease control and indirectly contribute to adherence problems.

These results highlight the importance of delivering cystinuria care through a coordinated multidisciplinary approach. Collaboration between pediatric nephrology, pediatric urology, and general pediatrics supports timely dose adjustments, structured monitoring of renal function, and early recognition of adverse effects. Because cystinuria requires lifelong management that often begins in early childhood, this type of coordinated follow-up is essential for preventing long-term renal deterioration.

Family education is equally important. Many potentially preventable dosing problems and early discontinuation patterns likely arise from gaps in caregiver understanding. Regular discussions with families during clinic visits can help reinforce key aspects of therapy, including the importance of accurate dosing, urinary alkalinization, recognizing adverse effects, and the goals of long-term treatment. Strengthening caregiver awareness has the potential to significantly improve both adherence and outcomes.

This FAERS-based analysis provides the first large-scale real-world overview of tiopronin safety. Tiopronin remains an indispensable treatment option for cystinuria, particularly in pediatric patients, but its effective long-term use depends on improved access, stronger caregiver support, and structured multidisciplinary follow-up.

Written by: Rifat Burak Ergül, MD,1,2,3,4 İsmail Taha Gürlek, MD,5 Şeyda Gül Özcan, MD,6 and Tzevat Tefik, MD1

  1. Department of Urology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye.
  2. EAU Young Academic Urologists (YAU) Urolithiasis and Endourology Working Group, Arnhem, Arnhem, NL-6803, The Netherlands.
  3. Department of Urology, Muş State Hospital, Muş, Türkiye.
  4. Varto Vocational School, Mus Alparslan University, Mus, Türkiye.
  5. Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye.
  6. Department of Nephrology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Türkiye.

References:

  1. Bhatt NP, Deshpande AV, Starkey MR. Pharmacological interventions for the management of cystinuria: a systematic review. Journal of Nephrology 37:293-308.
  2. Prot-Bertoye C, et al. Adverse events associated with currently used medical treatments for cystinuria and treatment goals: results from a series of 442 patients in France. BJU Int 124:849-861.
  3. Lindell A, Denneberg T, Jeppsson JO. Urinary excretion of free cystine and the tiopronin-cysteine-mixed disulfide during long-term tiopronin treatment of cystinuria. Nephron 71:328-342.
  4. Ergul et al. Treatment Compliance in Cystine Stone Patients. Journal of Endourology (Abstracts of the 41st World Congress of Endourology and Urotechnology), pp A234–A235.

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