The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency met on 8–11 June 2026 and adopted important recommendations for five safety signals. This article provides a comprehensive medical analysis of these signals: angioedema with darolutamide, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome with gemcitabine, neurodevelopmental disorders with paternal valproate exposure, fixed drug eruption with iodinated X-ray contrast agents, and protein-losing gastroenteropathy with zolbetuximab. For each signal, we explore the clinical presentation, pathophysiology, evidence base, regulatory actions, and practical implications for healthcare professionals, drawing on published literature and regulatory documents.
1. Introduction: The Role of PRAC in Medication Safety
The Pharmacovigilance Risk Assessment Committee (PRAC) is the European Medicines Agency’s committee responsible for evaluating safety signals for human medicines. At its meeting of 8–11 June 2026, PRAC adopted recommendations for five safety signals requiring updates to product information for both centrally and nationally authorised products. This article provides a detailed medical analysis of these signals, contextualising the regulatory findings with published literature and offering practical guidance for healthcare professionals.
2. Signal 1: Darolutamide – Angioedema
Signal EPITT No: 20237
PRAC Rapporteur: Not specified in extract
Action: Product information update (frequency “Not known”)
2.1 Background: Darolutamide
Darolutamide is a novel androgen receptor inhibitor indicated for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC). It works by blocking the action of androgens (such as testosterone and dihydrotestosterone), thereby stopping prostate cancer cells from growing and dividing. Unlike other androgen receptor inhibitors, darolutamide has a low blood-brain barrier penetration profile, potentially resulting in a more favourable neurological safety profile.
2.2 The Signal: Angioedema
PRAC identified a signal for angioedema associated with darolutamide. This is a new adverse reaction not previously listed in the product information. Angioedema is now being added to the product information with a frequency of “Not known”.
2.2.1 What is Angioedema?
Angioedema is a potentially life-threatening condition characterised by rapid swelling of the deeper layers of the skin and mucous membranes, often affecting the face, lips, tongue, throat, and extremities.
| Feature | Description |
|---|---|
| Definition | Rapid swelling of the subcutaneous and submucosal tissues due to increased vascular permeability |
| Mechanisms | Can be IgE-mediated (allergic), bradykinin-mediated (e.g., ACE inhibitors), or idiopathic |
| Clinical presentation | Swelling of face, lips, tongue, throat; may be accompanied by urticaria; laryngeal oedema can be life-threatening |
| Diagnosis | Clinical; may require exclusion of other causes |
| Treatment | Discontinuation of causative agent; antihistamines, corticosteroids, epinephrine (if anaphylaxis); C1-esterase inhibitor for hereditary angioedema |
2.2.2 Pathophysiological Considerations
The mechanism by which darolutamide may cause angioedema is not fully understood. However, several possibilities exist:
| Mechanism | Description |
|---|---|
| Immune-mediated | Drug-induced IgE-mediated hypersensitivity |
| Bradykinin-mediated | Interference with bradykinin metabolism (similar to ACE inhibitors) |
| Direct mast cell activation | Drug-induced mast cell degranulation |
Darolutamide is a P-glycoprotein (P-gp) inhibitor. Inhibition of P-gp may affect the clearance of other substrates, potentially leading to accumulation of substances that could trigger angioedema. However, the precise mechanism remains to be elucidated.
2.3 Regulatory Action
PRAC recommended that the Marketing Authorisation Holder (MAH) of darolutamide update the product information as follows:
Summary of Product Characteristics (SmPC) – Section 4.8
“Skin and subcutaneous tissue disorders: Frequency ‘Not known’: Angioedema (includes laryngeal oedema, lip swelling, swelling face, and swollen tongue). Spontaneous reports from post-marketing experience.”
Package Leaflet – Section 4
“Other side effects that have been reported with frequency not known (cannot be estimated from the available data): swelling under the skin in areas such as the face, lips, tongue and throat.”
2.4 Clinical Implications for Healthcare Professionals
| Implication | Action |
|---|---|
| Patient education | Counsel patients on darolutamide to recognise early signs of angioedema (swelling of face, lips, tongue, throat; difficulty breathing) |
| Emergency preparedness | Advise patients to seek immediate medical attention if symptoms develop |
| Reporting | Report any suspected cases of angioedema to national pharmacovigilance centres |
| Risk communication | Inform patients that angioedema is a rare but potentially serious side effect |
3. Signal 2: Gemcitabine – Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome
Signal EPITT No: 20256
PRAC Rapporteur: Not specified in extract
Action: Product information update (frequency “Not known”)
3.1 Background: Gemcitabine
Gemcitabine is a nucleoside analogue antimetabolite widely used in the treatment of various solid tumours, including pancreatic adenocarcinoma, non-small cell lung cancer, bladder cancer, and breast cancer. Its adverse effects are generally well characterised, predominantly haematological or infectious, while cutaneous reactions remain rare and usually mild. However, severe immune-mediated toxicities may occasionally occur.
3.2 The Signal: DRESS Syndrome
PRAC identified a signal for Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome associated with gemcitabine. This represents a new adverse reaction being added to the product information.
3.2.1 What is DRESS Syndrome?
DRESS is a rare, severe, and potentially life-threatening hypersensitivity reaction characterised by fever, diffuse cutaneous eruption, haematologic abnormalities (most notably eosinophilia), and multiorgan involvement, predominantly hepatic. According to a large literature review including 172 cases, DRESS carries a mortality rate of up to 10% .
3.2.2 DRESS and Gemcitabine: Case Reports
Published case reports support the association between gemcitabine and DRESS:
- Case 1: A 46-year-old man with nasopharyngeal carcinoma developed a febrile maculopapular rash with eosinophilia and hepatic cytolysis 15 days after the first cycle of gemcitabine-based chemotherapy. The diagnosis was established according to RegiSCAR criteria, and clinical improvement was achieved after discontinuation of gemcitabine and corticosteroid therapy.
- Case 2: A 60-year-old patient with pancreatic cancer and liver metastases developed fever, itching, and redness on the third day of receiving gemcitabine as a single agent.
These cases emphasise the importance of early recognition of atypical hypersensitivity reactions during chemotherapy and the need for immediate drug withdrawal to prevent potentially severe complications.
3.2.3 Pathophysiology
The pathophysiology of DRESS is thought to involve:
| Mechanism | Description |
|---|---|
| Drug-specific T-cell response | Activation of drug-specific CD8+ T cells |
| Viral reactivation | Reactivation of HHV-6, HHV-7, EBV, or CMV may play a role |
| Cytokine storm | Massive release of inflammatory cytokines |
| Metabolic factors | Slow drug metabolism or accumulation of reactive metabolites |
3.3 Regulatory Action
PRAC recommended that the MAH of gemcitabine update the product information as follows:
Summary of Product Characteristics (SmPC) – Section 4.4
“Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported in association with gemcitabine treatment… If signs and symptoms suggestive of these reactions appear, gemcitabine should be withdrawn immediately and an alternative treatment considered (as appropriate). If the patient has developed a severe cutaneous adverse reaction with the use of gemcitabine, treatment with gemcitabine must not be restarted at any time.”
SmPC – Section 4.8
“Skin and subcutaneous tissue disorders: Frequency: Not known: Drug reaction with eosinophilia and systemic symptoms (DRESS).”
Package Leaflet – Section 2 and Section 4
“Serious skin reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis (AGEP) have been reported… This medicine can cause serious skin reactions. Seek medical attention immediately if you notice any of the symptoms related to these serious skin reactions described in section 4.”
“Widespread rash, high body temperature and enlarged lymph nodes (DRESS syndrome or drug hypersensitivity syndrome) (frequency: not known).”
3.4 Clinical Implications for Healthcare Professionals
4. Signal 3: Valproate and Related Substances – Neurodevelopmental Disorders with Paternal Exposure
Signal EPITT No: 20191
PRAC Rapporteur: Not specified in extract
Action: Product information update
4.1 Background: Valproate
Valproate (valproic acid) is a broad-spectrum antiepileptic drug used for seizure disorders, bipolar disorder, and migraine prophylaxis. It is well established as a human teratogen, with well-documented risks of major congenital malformations and neurodevelopmental disorders following maternal exposure during pregnancy. However, the potential risk associated with paternal exposure has been less clear.
4.2 The Signal: Neurodevelopmental Disorders with Paternal Exposure
PRAC identified a signal concerning a possible increased risk of neurodevelopmental disorders (NDDs) in children born to men treated with valproate in the 3 months prior to conception.
4.2.1 The Evidence: Conflicting Studies
The evidence regarding paternal valproate exposure and NDDs is inconsistent:
4.2.2 Key Considerations
The PRAC assessment concluded that:
“Overall, the evidence regarding an increased risk of NDDs in children of fathers treated with valproate in the 3 months prior to conception is inconsistent, and the causal role of valproate is uncertain.”
Several factors may explain the differences in study findings:
4.3 Regulatory Action
PRAC recommended that the MAH of valproate-containing products update the product information to reflect the inconsistent evidence and uncertain causal role.
Summary of Product Characteristics (SmPC) – Section 4.4
“A retrospective observational study suggests an increased risk of neurodevelopmental disorders (NDDs) in children born to men treated with valproate in the 3 months prior to conception compared to those born to men treated with lamotrigine or levetiracetam. However, other studies do not suggest an increased risk of NDDs after paternal valproate exposure. Thus, available evidence is inconsistent and the causal role of valproate is uncertain.”
SmPC – Section 4.6
“Overall an increased risk of NDDs in children of fathers treated with valproate in the 3 months prior to conception is possible however the causal role of valproate is not confirmed.”
Package Leaflet – Section 2
“The risk for children born to fathers who stopped valproate treatment 3 months (the time needed to form new sperm) or longer before conception is not known. The study has limitations and therefore it is not clear if the increased risk for movement and mental developmental disorders suggested by this study is caused by valproate.”
4.4 Clinical Implications for Healthcare Professionals
| Implication | Action |
|---|---|
| Pre-conception counselling | Discuss the potential (but uncertain) risk with male patients taking valproate who are planning to father a child |
| Shared decision-making | Inform patients that the evidence is inconsistent and the causal role of valproate is uncertain |
| Consideration of alternatives | Where clinically appropriate, consider alternative anti-seizure medications (lamotrigine, levetiracetam) |
| Spermatogenesis cycle | Note that the risk for children born to fathers who stopped valproate 3 months or longer before conception is not known |
| Reporting | Report any suspected cases of NDDs in children of fathers exposed to valproate |
5. Signal 4: X-Ray Contrast Agents – Fixed Drug Eruption
Signal EPITT No: 20229
PRAC Rapporteur: Not specified in extract
Action: Product information update (frequency “Not known”)
5.1 Background
Iodinated contrast media (ICM) are widely used for diagnostic imaging, including computed tomography (CT) scans, angiography, and intravenous urography. The agents covered by this signal include: iobitridol, iodixanol, iohexol, iomeprol, iopamidol, iopromide, ioversol, and ioxitalamic acid.
ICM can induce both immediate-onset (IgE-mediated) and delayed-onset (T-cell-mediated) hypersensitivity reactions. Delayed reactions typically occur 1–7 days after exposure and are more common with non-ionic monomers.
5.2 The Signal: Fixed Drug Eruption
PRAC identified a signal for fixed drug eruption (FDE) associated with iodinated X-ray contrast agents.
5.2.1 What is Fixed Drug Eruption?
Fixed drug eruption is a distinctive type of cutaneous adverse drug reaction that occurs through a type IV hypersensitivity mechanism (T-cell-mediated). It is characterised by well-demarcated red-brown patches that reappear at the same anatomical site(s) following re-exposure to the offending medication.
| Feature | Description |
|---|---|
| Incubation period | Typically 24–48 hours after re-exposure |
| Clinical presentation | Well-demarcated, round or oval, erythematous to hyperpigmented patches or plaques; may be bullous; often pruritic or burning |
| Common sites | Genitalia, lips, hands, feet, trunk |
| Pathophysiology | Type IV hypersensitivity; skin-resident memory T cells play a crucial role |
| Diagnosis | Clinical; rechallenge is diagnostic but carries risk; patch testing may be helpful |
| Management | Identification and avoidance of the causative drug; topical corticosteroids for symptomatic relief |
5.2.2 ICM-Induced Fixed Drug Eruption: Evidence
ICM-induced FDE is rare but increasingly recognised:
- There have been 10 reported cases of FDE secondary to ICM identified in the literature. Six occurred following a CT scan, and the culprit ICM in over half of cases was a non-ionic monomeric medium.
- A case report described a 69-year-old woman who developed a widespread painful blistering rash with well-demarcated erosions a few hours after a CT scan performed with iohexol. The diagnosis was generalised bullous fixed drug eruption secondary to iohexol. Strikingly, each episode occurred within 24 hours following ICM administration and was self-limiting in nature.
- Delayed eruptions are primarily T-cell-mediated, and their pathophysiology often mimics severe cutaneous adverse reactions. Among these delayed reactions, FDE and iododerma are rare and frequently misdiagnosed.
5.2.3 Pathophysiology
ICM-induced FDE is a non-immediate, T-cell-mediated hypersensitivity reaction. Skin-resident memory T cells play a crucial role in the localised recurrence at the same site.
5.3 Regulatory Action
PRAC recommended that the MAHs of the affected contrast agents update the product information as follows:
Summary of Product Characteristics (SmPC) – Section 4.8
“Skin and subcutaneous tissue disorders: Frequency ‘Not known’: Fixed drug eruption.”
Package Leaflet – Section 4
“Side effects reported/described with frequency ‘Not known’ (frequency cannot be estimated from the available data): An allergic skin reaction that may include round or oval patches of redness and swelling of the skin, blistering, and itching (fixed drug eruption). Darkening of the skin in affected areas, which might persist after healing, may also occur. Fixed drug eruption usually reoccurs at the same site(s) if the medication is taken again.”
5.4 Clinical Implications for Healthcare Professionals
| Implication | Action |
|---|---|
| History taking | Ask about prior contrast reactions before administration; document the location and nature of any previous reactions |
| Site identification | Document the location of previous reactions to aid in diagnosis |
| Prevention | Avoid re-exposure to the same contrast agent; consider alternative if clinically necessary |
| Management | Treat with topical or systemic corticosteroids as needed; provide symptomatic relief |
| Patient education | Counsel patients to report any recurrence of skin lesions at the same site with repeated contrast exposure |
| Reporting | Report any suspected cases of FDE following contrast administration |
6. Signal 5: Zolbetuximab – Protein-Losing Gastroenteropathy
Signal EPITT No: 20236
PRAC Rapporteur: Not specified in extract
Action: Product information update (frequency “Not known”)
6.1 Background: Zolbetuximab
Zolbetuximab is a monoclonal antibody targeting Claudin-18.2, a tight junction protein expressed on gastric epithelial cells. It is a promising therapeutic agent for the treatment of advanced gastric cancer. Its anticancer effects occur through a variety of mechanisms, including antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.
6.2 The Signal: Protein-Losing Gastroenteropathy
PRAC identified a signal for protein-losing gastroenteropathy associated with zolbetuximab.
6.2.1 What is Protein-Losing Gastroenteropathy?
Protein-losing gastroenteropathy is a condition characterised by excessive loss of plasma proteins (including albumin and immunoglobulins) into the gastrointestinal tract, leading to hypoalbuminaemia, oedema, and hypogammaglobulinaemia.
| Feature | Description |
|---|---|
| Definition | Excessive loss of plasma proteins into the gastrointestinal tract |
| Mechanisms | Increased mucosal permeability, lymphatic obstruction, mucosal injury |
| Clinical presentation | Peripheral oedema, ascites, hypoalbuminemia, hypogammaglobulinemia, weight loss, diarrhoea |
| Diagnosis | Elevated faecal alpha-1 antitrypsin clearance; protein leakage scintigraphy (99mTc-HSA-D) |
| Treatment | Treatment of underlying cause; nutritional support; albumin infusion if severe |
6.2.2 Zolbetuximab-Induced Protein-Losing Gastroenteropathy: Evidence
A 2025 case report described the first case of zolbetuximab-induced protein-losing gastroenteropathy in a patient with advanced gastric cancer.
Case Details:
- A 41-year-old woman with metastatic Claudin-18.2-positive gastric cancer was treated with zolbetuximab in combination with chemotherapy
- On day 8 of the second treatment cycle, she developed severe gastrointestinal symptoms and immunologic abnormalities
- Laboratory tests revealed marked hypogammaglobulinemia (IgG 193 mg/dL) and hypoalbuminemia (albumin 1.9 g/dL)
- Esophagogastroduodenoscopy showed severe acute gastritis
- Biopsy specimens demonstrated infiltration of CD4+ lymphocytes into the stroma and CD8+ lymphocytes into both the epithelium and stroma, as well as IgA deposition along interstitial capillaries
- Protein leakage from the stomach was confirmed by 99mTc-HSA-D scintigraphy
Proposed Mechanism:
“ZOL-induced mucosal injury and increased vascular permeability, likely driven by an IgA-mediated vasculitic mechanism, contributed to the protein loss.”
Rechallenge Evidence:
Upon zolbetuximab rechallenge, gastrointestinal symptoms and protein loss recurred in a milder form, reinforcing a causal relationship.
6.3 Regulatory Action
PRAC recommended that the MAH of zolbetuximab update the product information as follows:
Summary of Product Characteristics (SmPC) – Section 4.8
“Gastrointestinal disorders: Gastritis (frequency: uncommon); Protein-losing gastroenteropathy (frequency: not known).”
Package Leaflet – Section 4
“Other side effects that have been reported with frequency not known (cannot be estimated from the available data): Loss of protein from the digestive tract (protein-losing gastroenteropathy).”
6.4 Clinical Implications for Healthcare Professionals
7. Summary of PRAC Actions
| Drug | Signal | PRAC Action | Clinical Severity | Expected Outcome |
|---|---|---|---|---|
| Darolutamide | Angioedema | Product information update (frequency “Not known”) | High (potentially life-threatening) | SmPC and PIL update |
| Gemcitabine | DRESS syndrome | Product information update (frequency “Not known”) | High (mortality up to 10%) | SmPC and PIL update with withdrawal advice |
| Valproate (paternal exposure) | Neurodevelopmental disorders | Product information update | Moderate (uncertain causality) | SmPC and PIL update reflecting inconsistent evidence |
| Iodinated contrast agents | Fixed drug eruption | Product information update (frequency “Not known”) | Moderate | SmPC and PIL update |
| Zolbetuximab | Protein-losing gastroenteropathy | Product information update (frequency “Not known”) | Moderate to high | SmPC and PIL update |
8. Practical Guidance for Healthcare Professionals
8.1 Recognizing and Reporting Adverse Reactions
| Signal | Red Flags | Diagnostic Steps | Management |
|---|---|---|---|
| Angioedema (darolutamide) | Swelling of face, lips, tongue, throat; difficulty breathing | Clinical examination; exclude other causes | Discontinue drug; antihistamines, corticosteroids; epinephrine if anaphylaxis; report |
| DRESS syndrome (gemcitabine) | Fever, rash, eosinophilia, hepatic cytolysis; onset 2-6 weeks after drug initiation | RegiSCAR criteria; liver function tests; eosinophil count; skin biopsy | Discontinue gemcitabine permanently; systemic corticosteroids; specialist referral; report |
| NDDs (paternal valproate) | Concern about child development; father on valproate | Neurodevelopmental assessment; review medication history | Pre-conception counselling; consider alternative ASMs; report |
| Fixed drug eruption (contrast agents) | Well-demarcated lesions at same site with re-exposure; history of prior contrast reaction | Clinical examination; patch testing may help; rechallenge is diagnostic | Avoid re-exposure; consider alternative contrast agent; topical corticosteroids; report |
| Protein-losing gastroenteropathy (zolbetuximab) | Oedema, hypoalbuminaemia, hypogammaglobulinaemia; gastrointestinal symptoms | Serum albumin and immunoglobulin levels; faecal alpha-1 antitrypsin; scintigraphy; endoscopy | Supportive care; nutritional support; consider rechallenge carefully; report |
8.2 The Importance of Reporting
Each of these signals was identified because healthcare professionals and manufacturers reported suspected adverse reactions. Healthcare professionals play a vital role in:
- Recognising potential adverse reactions
- Documenting cases thoroughly
- Reporting to national pharmacovigilance centres
- Contributing to the global knowledge base
9. Conclusion
The June 2026 PRAC recommendations highlight the dynamic nature of pharmacovigilance and the ongoing need for post-marketing safety surveillance. The five signals discussed in this article demonstrate the diverse ways in which adverse reactions can manifest:
- Darolutamide – angioedema, a potentially life-threatening hypersensitivity reaction
- Gemcitabine – DRESS syndrome, a severe drug reaction with significant mortality
- Valproate – potential but uncertain risk of NDDs with paternal exposure, highlighting the importance of ongoing pharmacoepidemiological research
- Iodinated contrast agents – fixed drug eruption, a distinctive T-cell-mediated reaction
- Zolbetuximab – protein-losing gastroenteropathy, a novel adverse effect mediated by IgA vasculitis
For healthcare professionals, these updates serve as important reminders to:
- Maintain clinical vigilance for emerging safety signals
- Consider drug-induced aetiologies in differential diagnosis
- Document and report suspected adverse reactions
- Stay informed through regulatory communications
Each report contributes to the global understanding of drug safety and may help identify signals that protect future patients.
