Rare diseases in pediatrics represent a unique challenge within the healthcare landscape. Defined as conditions affecting fewer than 1 in 2,000 individuals in Europe, these disorders collectively impact millions of children worldwide. However, the treatment of rare pediatric diseases occurs within a complex pharmacovigilance framework characterised by limited pre-authorisation safety data, significant off-label prescribing, and unique vulnerability to adverse drug reactions.
This article provides a comprehensive examination of the intersection between rare pediatric diseases and pharmacovigilance, exploring both the phenomenon of drug-induced rare diseases and the safety profiles of orphan drugs used to treat these conditions. Drawing on data from the World Health Organization, the U.S. Food and Drug Administration, the European Medicines Agency, and recent pharmacovigilance literature, we analyse the mechanisms, risks, and management strategies for adverse drug reactions in this vulnerable population.
1. Introduction: The Unique Challenge of Rare Pediatric Diseases
Rare diseases, defined in Europe as conditions affecting fewer than 1 in 2,000 people, represent a significant public health challenge. While each individual disease is uncommon, collectively they affect approximately 30 million people in the European Union alone. In pediatrics, rare diseases are particularly devastating, often presenting in infancy or early childhood with severe, progressive, and life-limiting consequences.
The pharmacovigilance landscape for rare pediatric diseases is uniquely challenging. As noted in an EMA concept paper, many medicines used to treat children are not licensed for such use (off-label use) or are not licensed at all (unlicensed use), which may further limit reporting of suspected adverse reactions to pharmacovigilance systems.
Furthermore, many of the products developed for rare childhood diseases have limited safety and efficacy data at the time of licensing. Children may have different pharmacokinetics and dynamics compared to adults and therefore have particular vulnerability to adverse drug reactions. Children are growing and may therefore be susceptible to developmental disorders, as well as delayed ADRs not seen in adults.
2. Drug-Induced Rare Diseases in Pediatrics
2.1 The Phenomenon of Drug-Induced Rare Diseases
Medications can, in susceptible individuals, induce rare diseases or rare adverse events that mimic spontaneous rare diseases. In pediatrics, this phenomenon is particularly concerning due to the developing nature of children’s organ systems and their unique metabolic profiles.
The French Network of Regional Pharmacovigilance Centres has emphasised the importance of close collaboration between rare disease reference centres and pharmacovigilance centres. Through several historical examples, clinicians from rare disease reference centres can easily report adverse drug reactions (ADRs) to pharmacologists from their regional pharmacovigilance centre. This collaborative model has been instrumental in identifying drug-induced rare diseases.
2.2 Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are rare but life-threatening mucocutaneous reactions most often induced by drugs. These conditions represent a classic example of drug-induced rare diseases in pediatrics.
A comprehensive analysis of the WHO pharmacovigilance database (VigiBase) identified drugs associated with paediatric SJS-TEN. The study found that the five drugs with the highest information component (IC025) values were lamotrigine (IC025 4.99), carbamazepine (IC025 4.88), phenobarbital (IC025 4.67), phenytoin (IC025 4.52) and nimesulide (IC025 4.23).
A retrospective cross-sectional analysis of the U.S. FDA’s FAERS database examined 2,673 pediatric reports of SJS/TEN. Key findings included:
- 67.4% involved SJS and 32.6% involved TEN
- The majority (62.3%) were in the 0-11 age group
- Nervous system agents—especially antiepileptics—were predominantly associated with older children
- Systemic anti-infectives such as amoxicillin, azithromycin, and cefaclor were more frequent in younger children
- Lamotrigine showed both age groups and female predominance
- Paracetamol and ibuprofen were significantly associated with the TEN phenotypes in younger males
These findings emphasise the importance of age-stratified pharmacovigilance and cautious prescribing of high-risk drugs such as lamotrigine and antibiotics.
2.3 Drug-Induced Liver Injury
Drug-induced liver injury (DILI) in children is a rare, underdiagnosed cause of liver disease. Pediatric hepatic ADR reports constituted only 2.9% of total ADRs, but the majority (77.5%) were serious adverse outcomes. The most common hepatotoxic drugs in children are antibiotics and antiepileptics. DILI is classified as intrinsic or idiosyncratic and presents mostly with hepatocellular or cholestatic patterns of injury.
Propylthiouracil (PTU) has been associated with serious liver injury, including liver failure and death. The FDA identified 32 AERS cases (22 adult and 10 pediatric) of serious liver injury associated with propylthiouracil use. Among the pediatric patients, 1 case resulted in death and 6 in liver transplants.
2.4 Drug-Induced Aplastic Anemia
Aplastic anemia, a rare but life-threatening condition characterised by bone marrow failure, can be induced by medications. Chloramphenicol has been historically associated with fatal aplastic anemia in children. Valproic acid has also been reported to induce aplastic crisis and Stevens-Johnson syndrome in a single pediatric patient.
A pharmacovigilance assessment of drug-induced aplastic anemia using the FDA Adverse Event Reporting System identified key drugs and patient factors associated with aplastic anemia, providing a data-driven framework for pharmacovigilance.
2.5 Drug-Induced Pulmonary Arterial Hypertension
Fenfluramine, an anti-epileptic drug approved for Dravet syndrome and Lennox-Gastaut syndrome, has been associated with pulmonary arterial hypertension (PAH) in pediatric patients. A case report described a child under two years of age with SCN1B-related DEE who developed asymptomatic fenfluramine-associated PAH after one year of treatment.
Notably, published randomised controlled trials and open-label extensions have not reported clinically significant PAH in patients aged two years or older. This case emphasises the rare occurrence of fenfluramine-associated PAH in children under two years of age and underscores the importance of vigilant cardiac surveillance in this population.
Dasatinib-induced reversible pulmonary arterial hypertension has also been reported in a pediatric patient with BCR/ABL1+ lymphoblastic lymphoma.
2.6 Drug-Induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome
DRESS syndrome, also known as drug hypersensitivity syndrome, is a severe, potentially life-threatening adverse drug reaction characterised by rash, fever, lymphadenopathy, eosinophilia, and systemic organ involvement. A narrative review reported the latest evidence about the diagnosis and treatment of pediatric DRESS syndrome.
Ethosuximide has been associated with DILI-DRESS in a pediatric patient with vanishing bile ducts syndrome.
3. Pharmacovigilance of Orphan Drugs in Pediatrics
3.1 The Therapeutic Orphan Problem
Historically, children have been described as “therapeutic orphans” because the majority of drugs used in child healthcare were used off-label. This has significant pharmacovigilance implications: off-label medicine use in paediatric patients leads to a greater risk of medication error, in turn leading to a higher risk of developing an adverse drug reaction (ADR) than in adults.
3.2 Regulatory Framework and Post-Marketing Surveillance
The European Medicines Agency (EMA) has emphasised the need for effective pharmacovigilance for children’s medicines. Key issues identified include:
- Childhood diseases may be qualitatively and quantitatively different from adult diseases
- Efficacy in children cannot always be assumed from adult efficacy data
- Children may have different pharmacokinetics and dynamics to adults and therefore have particular vulnerability to ADRs
- Children may have different drug metabolism and consequently a different drug interaction profile compared to adults
- Children are growing and may therefore be susceptible to developmental disorders, as well as delayed ADRs not seen in adults
The EMA concept paper notes that the first products with orphan medicinal product status are now being authorised in the EU. Many of these products will be for rare childhood diseases and the data on safety and efficacy at the time of licensing is likely to be limited in several cases.
3.3 Trofinetide in Rett Syndrome
Trofinetide, a synthetic analog of glycine-proline-glutamate, is the first FDA-approved treatment for Rett syndrome, a rare X-linked neurodevelopmental disorder with an estimated prevalence of 1 in 10,000 to 15,000 live female births.
A real-world postmarketing pharmacovigilance study of trofinetide in pediatric Rett syndrome patients using the FAERS database (Q1 2023 to Q4 2024) provided critical safety data:
Common labelled AEs confirmed:
Off-label/new signals identified:
- Weight decreased: n = 135; ROR = 7.21
- Tremor: n = 39; ROR = 3.37
- Dystonia: n = 18; ROR = 4.39
- Dyskinesia: n = 24; ROR = 4.53
Key findings:
- Over 70% of AEs occurred within the first month
- Hypersomnia was more frequently reported in younger children (ROR = 12.11)
- Higher doses were associated with psychiatric symptoms
This study highlights the importance of monitoring dose-related and age-specific adverse events in clinical settings.
3.4 Cerliponase Alfa in CLN2 Disease
Cerliponase alfa is a recombinant human tripeptidyl peptidase 1 enzyme replacement therapy for Neuronal Ceroid Lipofuscinosis type 2 (CLN2), a rare neurodegenerative disorder. A descriptive analysis of real-world spontaneous reporting data of suspected adverse reactions to cerliponase alfa in the EudraVigilance database revealed:
- Cases were more frequent in female patients (58.1%) and in children aged 3–11 years
- The most common adverse reactions were, in decreasing order: fever/pyrexia, device-related infection, vomiting, seizures/convulsions, pleocytosis, irritability, ventriculitis, and respiratory disorders
The study concluded that the results confirm the safety profile of cerliponase alfa established with pre-registration clinical studies but suggest the need for further studies to investigate the occurrence of adverse reactions as possible predictive prognostic markers.
3.5 Onasemnogene Abeparvovec (Zolgensma) in Spinal Muscular Atrophy
Onasemnogene abeparvovec, an adeno-associated virus vector-based gene therapy for spinal muscular atrophy, has been subject to pharmacovigilance analysis using the EMA Adverse Event Reporting System. Out of a total of 2,744 reported ADRs, the most commonly reported adverse reactions were:
- Increased hepatic enzymes
- Pyrexia
- Vomiting
- Thrombocytopenia
Serious adverse events included cardiac arrest (n = 8; 6.2%), respiratory arrest or respiratory failure (both n = 5; 3.8%).
3.6 Tiopronin in Cystinuria
Tiopronin is used in the treatment of cystinuria, a rare genetic disorder that causes recurrent cystine stones and significant morbidity, particularly in children. The first real-world pharmacovigilance analysis of tiopronin safety using the FAERS database has been published, providing crucial safety data for this rare disease population.
4. Treatment-Related Adverse Effects: Management Strategies
4.1 General Principles of ADR Management in Rare Pediatric Diseases
| Step | Action | Description |
|---|---|---|
| 1. Identification | Recognise the ADR | Monitor for signs/symptoms; distinguish from disease progression |
| 2. Assessment | Determine causality and severity | Use standardised tools (e.g., Naranjo scale, Liverpool Causality Assessment Tool) |
| 3. Documentation | Record in medical record and ADR database | Essential for pharmacovigilance |
| 4. Reporting | Report to national pharmacovigilance centre | Critical for signal detection |
| 5. Intervention | Manage the reaction | Dose adjustment, supportive care, or discontinuation |
| 6. Prevention | Prevent recurrence | Pre-emptive measures; avoid re-exposure |
4.2 Specific Management Strategies for Common ADRs
| ADR Type | Management Approach |
|---|---|
| Gastrointestinal (diarrhoea, vomiting) | Supportive care (hydration, antiemetics); dose reduction or temporary interruption |
| Hepatic enzyme elevation | Monitor LFTs; consider dose adjustment; evaluate for DILI |
| Immunosuppression/infections | Prophylactic antimicrobials; monitor for signs of infection |
| Cardiotoxicity | Echocardiographic monitoring; cardioprotective measures |
| Neurotoxicity | Dose reduction/discontinuation; symptomatic treatment |
| Hypersensitivity | Premedication; desensitisation protocols; alternative agents |
4.3 Special Considerations for Gene Therapies
The FDA has issued safety communications regarding serious adverse events associated with gene therapies for rare pediatric diseases:
- ELEVIDYS (delandistrogene moxeparvovec) for Duchenne Muscular Dystrophy: The FDA received two reports of fatal acute liver failure following treatment of non-ambulatory pediatric male patients. The reports were received from clinical trial and postmarketing data, and the patients presented with elevated transaminases and were hospitalised less than two months after treatment. The FDA is investigating the risk of acute liver failure with serious outcomes.
- Kygevvi (doxecitine and doxribtimine) for thymidine kinase 2 deficiency: The most common side effects are diarrhoea, vomiting, increase in liver enzymes, and abdominal pain.
5. The Role of Pharmacovigilance in Rare Pediatric Diseases
5.1 Challenges in Signal Detection
Signal detection in rare pediatric diseases presents unique challenges:
5.2 Pharmacovigilance Strategies
5.3 The Importance of Age-Stratified Pharmacovigilance
The study of pediatric SJS/TEN from the FAERS database emphasises the importance of age-stratified pharmacovigilance. Age-specific differences in drug associations were observed:
- Younger children (0-11 years): more frequently associated with anti-infectives
- Older children (12-17 years): more frequently associated with antiepileptics
These findings highlight the need for cautious prescribing of high-risk drugs and better awareness of potential biases, such as protopathic misattribution, which is crucial for accurate signal detection in pediatric pharmacovigilance.
Recommendations for Healthcare Professionals
Clinical Practice
| Recommendation | Rationale |
|---|---|
| Maintain high suspicion for ADRs | Rare diseases and their treatments can both present with unusual manifestations |
| Use age-appropriate dosing | Children have different pharmacokinetics and may be more susceptible to ADRs |
| Monitor for delayed effects | Children are growing and may develop ADRs not seen in adults |
| Document and report ADRs | Essential for signal detection in rare disease populations |
| Engage with pharmacovigilance centres | Collaborate with experts to characterise and manage ADRs |
Pharmacovigilance Practice
Conclusion
The intersection of rare diseases, pediatrics, and pharmacovigilance presents a complex challenge requiring a multidisciplinary approach. Medications can both cause rare diseases (as exemplified by drug-induced SJS/TEN, DILI, aplastic anaemia, and PAH) and cause adverse effects when used to treat rare diseases (as demonstrated by the safety profiles of orphan drugs such as trofinetide, cerliponase alfa, and onasemnogene abeparvovec).
Key takeaways include:
- Drug-induced rare diseases are a significant concern in pediatrics, with antiepileptics and anti-infectives being common culprits.
- Orphan drugs require rigorous post-marketing surveillance because safety data at the time of licensing is often limited.
- Age-stratified pharmacovigilance is essential as drug associations and ADR profiles differ between younger and older children.
- Gene therapies present novel safety challenges, including acute liver failure and other serious adverse events.
- Reporting of suspected ADRs is critical for signal detection and patient safety.
The EMA has emphasised that there is a need to carefully consider how pharmacovigilance is conducted for medicines used by children and whether there are any aspects of the pharmacovigilance system that need to be enhanced to ensure adequate protection of public health. This is particularly true for rare pediatric diseases, where the combination of limited safety data and vulnerable patient populations demands the highest standards of vigilance.
References
- European Medicines Agency. Concept paper on conduct of pharmacovigilance for medicines used by children. CPMP/PhVWP/4838/02. London, 17 October 2002.
- Bataille P, Lebrun-Vignes B, Bettuzzi T, et al. Drugs associated with epidermal necrolysis in children: A World Health Organization pharmacovigilance database analysis. J Eur Acad Dermatol Venereol. 2024;38(9):1791-1798.
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- Safety Profiles of Trofinetide in Pediatric Rett Syndrome Population: A Real-World Postmarketing Pharmacovigilance Analysis. Clinical Therapeutics. Volume 47, Issue 10, October 2025, Pages 859-866.
- Adverse Reactions to the Orphan Drug Cerliponase Alfa in the Treatment of Neurolipofuscinosis Type 2 (CLN2). Pharmaceuticals. 2024;17(11):1513.
- Real-World Safety Data of the Orphan Drug Onasemnogene Abeparvovec (Zolgensma®) for the SMA Rare Disease: A Pharmacovigilance Study Based on the EMA Adverse Event Reporting System. 2024.
- FDA. FDA approves 1st drug for thymidine kinase 2 deficiency. November 2025.
- FDA. FDA Investigating Deaths Due to Acute Liver Failure in Non-ambulatory Duchenne Muscular Dystrophy Patients Following ELEVIDYS. FDA Safety Communication, June 24, 2025.
- Pharmacovigilance assessment of drug-induced aplastic anemia: analysis of the FDA adverse event reporting system.
- Reversible Pulmonary Arterial Hypertension Due to Fenfluramine in a Young Child: A Case Report. 2026.
- Tiopronin safety in cystinuria: first real-world pharmacovigilance analysis using the FDA Adverse Event Reporting System (FAERS). Pediatr Nephrol. 2026;41(4):1087.
- Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase.
