The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency meets monthly to evaluate safety signals for medicinal products and recommend appropriate regulatory actions. At its meeting of 12–15 January 2026, PRAC adopted important recommendations concerning three distinct medicinal products: the antibiotic cefazolin, the antineoplastic erdafitinib, and pegylated liposomal doxorubicin.
The signals include a new safety concern for a well-established drug (Kounis syndrome with cefazolin), a previously unknown paediatric risk (growth acceleration and epiphysiolysis with erdafitinib), and a rare renal adverse event (renal‑limited thrombotic microangiopathy with pegylated liposomal doxorubicin). In addition, PRAC requested supplementary information for several other signals, including strabismus with atropine eye drops, angioedema with darolutamide, DRESS syndrome with oxacillin, acute pancreatitis with vortioxetine, fixed drug eruption with X‑ray contrast agents, protein‑losing gastroenteropathy with zolbetuximab, and suicidal ideation with zuranolone.
1. Introduction: The Role of PRAC in Medication Safety
The Pharmacovigilance Risk Assessment Committee (PRAC) is the European Medicines Agency’s committee responsible for assessing and monitoring safety issues for human medicines. Composed of experts from EU Member States, PRAC plays a critical role in:
Requesting supplementary information from marketing authorisation holders (MAHs)
- Detecting and evaluating safety signals
- Assessing risk management plans
- Evaluating periodic safety update reports
- Making recommendations for product information updates
At its meeting of 12–15 January 2026, PRAC evaluated multiple safety signals and adopted recommendations ranging from product information updates to requests for supplementary information.
2. Recommendations for Product Information Updates
2.1 Cefazolin – Kounis Syndrome
Signal EPITT No: 20204
PRAC Rapporteur: Sonja Radowan (AT)
2.1.1 Background
Cefazolin is a first-generation cephalosporin antibiotic widely used for surgical prophylaxis and treatment of various bacterial infections. It is often administered in combination with lidocaine hydrochloride for intramuscular injection to reduce injection site pain.
2.1.2 What is Kounis Syndrome?
Kounis syndrome is defined as the concurrence of acute coronary syndromes with conditions associated with mast cell activation, including allergic or hypersensitivity reactions . It represents a critical intersection between allergy and cardiology.
Pathophysiology:
Allergic or hypersensitivity reactions trigger mast cell degranulation, releasing inflammatory mediators including histamine, leukotrienes, prostaglandins, and various cytokines. These mediators cause coronary artery vasospasm, plaque erosion/rupture, or stent thrombosis, leading to reduced coronary blood flow and potentially myocardial infarction .
Three Types of Kounis Syndrome:
| Type | Description |
|---|---|
| Type I | Occurs in patients with normal coronary arteries; acute release of inflammatory mediators causes coronary vasospasm |
| Type II | Occurs in patients with pre-existing coronary artery disease; mediators cause plaque erosion or rupture |
| Type III | Occurs in patients with coronary stents; mediators cause in-stent thrombosis |
2.1.3 Evidence for Cefazolin-Associated Kounis Syndrome
A case report published in 2018 documented Kounis syndrome caused by anaphylaxis without skin manifestations after cefazolin administration . The case highlights that allergic reactions to cefazolin may present with cardiovascular symptoms even in the absence of typical cutaneous manifestations.
Clinical Presentation:
Patients may present with:
- Chest pain (often acute onset)
- ST-segment changes on ECG
- Elevated cardiac enzymes
- Concurrent allergic symptoms (may be subtle or absent)
- Dyspnoea, hypotension, tachycardia
2.1.4 Regulatory Action
PRAC recommended that Marketing Authorisation Holders (MAHs) of cefazolin-containing products submit a variation within two months to amend product information.
SmPC Section 4.4 (Special warnings and precautions for use):
“Cases of Kounis syndrome have been reported in patients treated with cefazolin. Kounis syndrome has been defined as cardiovascular symptoms secondary to an allergic or hypersensitive reaction associated with constriction of coronary arteries and potentially leading to myocardial infarction.”
Package Leaflet Section 2:
“Signs of an allergic reaction to this medicine, including breathing problems and chest pain, have been reported with cefazolin. Stop immediately cefazolin and contact immediately your doctor or medical emergencies if you notice any of these signs.”
2.1.5 Clinical Implications
| Implication | Action |
|---|---|
| Awareness | Recognize that chest pain during or after cefazolin administration may represent Kounis syndrome, not simply a “reaction” |
| Differential diagnosis | Consider Kounis syndrome in any patient presenting with acute coronary symptoms following antibiotic administration |
| Immediate management | Stop the drug immediately; manage as both allergic reaction and acute coronary syndrome |
| Reporting | Report suspected cases to national pharmacovigilance centres |
2.2 Erdafitinib – Growth Acceleration
Signal EPITT No: 20194
PRAC Rapporteur: Bianca Mulder (NL)
2.2.1 Background
Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor indicated for the treatment of urothelial carcinoma in adults. It is not authorised for use in paediatric patients.
2.2.2 The Signal: Growth Acceleration and Epiphysiolysis
PRAC identified a safety signal concerning growth acceleration and epiphysiolysis of the femoral head in paediatric patients exposed to erdafitinib, observed in clinical trials outside the authorised indication and in off-label post-marketing use.
2.2.3 Pathophysiology: FGFR Inhibition and Skeletal Growth
A 2024 study by Hartmann and colleagues provides crucial insights into the mechanism . The authors reported on paediatric patients with CNS tumours treated with erdafitinib under a compassionate-use program who experienced unanticipated growth acceleration.
Key Mechanistic Findings:
| Observation | Implication |
|---|---|
| Growth acceleration independent of sex steroids and IGF1 | Suggests direct effect on growth plate rather than hormonal stimulation |
| Distinct widening of the growth plate | Indicates FGFR3 inhibition—FGFR3 normally acts as a negative regulator of bone growth |
| Enhanced metaphyseal mineralization | Suggests altered bone remodeling |
Therapeutic Paradox: Erdafitinib inhibits FGFR3, which normally limits bone growth. Mutations activating FGFR3 cause achondroplasia, while inhibition of this receptor promotes growth. This explains the observed growth acceleration .
2.2.4 Epiphysiolysis of the Femoral Head
Epiphysiolysis (slipped capital femoral epiphysis) is a condition where the femoral head slips relative to the femoral neck through the growth plate. During periods of rapid growth, the growth plate becomes vulnerable to mechanical stress.
Clinical Presentation:
- Hip, groin, thigh, or knee pain (referred pain is common)
- Antalgic limp
- Limited internal rotation of the hip
- May be acute or chronic
2.2.5 Regulatory Action
PRAC recommended that the MAH (Janssen-Cilag International N.V.) submit a variation within two months to amend product information.
SmPC Section 4.8:
“Paediatric population: Growth acceleration and epiphysiolysis of the femoral head have been reported in paediatric patients (<18 years of age) receiving erdafitinib in clinical trials outside of the authorised indication and off label in the post-marketing setting.”
Package Leaflet:
“Balversa may cause accelerated growth or irregular hip joint growth or damage in paediatric patients (<18 years of age). If you or your child experience pain in the hip or knee or have an unexplained limp, talk to your doctor.”
2.2.6 Clinical Implications
| Implication | Action |
|---|---|
| Off-label use warning | Erdafitinib should not be used in paediatric patients except in approved clinical trials |
| Monitoring | If a paediatric patient has been exposed, monitor for hip/knee pain, limp, and growth changes |
| Patient education | Advise patients/carers to report any unexplained limp or hip/knee pain immediately |
| Orthopaedic referral | Suspected epiphysiolysis requires urgent orthopaedic evaluation |
2.3 Pegylated Liposomal Doxorubicin – Renal-Limited Thrombotic Microangiopathy
Signal EPITT No: 20193
PRAC Rapporteur: Eva Jirsová (CZ)
2.3.1 Background
Doxorubicin is an anthracycline antibiotic used in cancer chemotherapy. Pegylated liposomal doxorubicin (PLD) is a formulation where the drug is encapsulated in liposomes coated with polyethylene glycol (PEG), which prolongs circulation time, alters biodistribution, and reduces cardiotoxicity compared to conventional doxorubicin.
2.3.2 What is Renal-Limited Thrombotic Microangiopathy?
Thrombotic microangiopathy (TMA) is a pathological condition characterised by microvascular thrombosis, microangiopathic haemolytic anaemia, thrombocytopenia, and end-organ damage.
Renal-Limited TMA refers to TMA confined to the kidneys, without systemic features:
| Feature | Classic Systemic TMA | Renal-Limited TMA |
|---|---|---|
| Kidney involvement | Present | Present |
| Neurological symptoms | Often present | Absent |
| Thrombocytopenia | Typically present | May be mild or absent |
| Haemolytic anaemia | Typically present | May be mild or absent |
| Diagnosis | Clinical + laboratory | May require kidney biopsy |
2.3.3 Evidence for PLD-Induced Renal-Limited TMA
A 2023 case report published in the American Journal of Kidney Diseases established a clear causal link between PLD and kidney-limited TMA . The authors described two cases:
| Case | Patient | Cumulative PLD Dose | Presentation | Outcome |
|---|---|---|---|---|
| Case 1 | 72-year-old female, myxofibrosarcoma | High cumulative dose | Rising creatinine, proteinuria; biopsy showed TMA with chronic mesangiolysis | Improvement after PLD cessation |
| Case 2 | Patient with liposarcoma | High cumulative dose | Similar presentation | Stabilization after PLD cessation |
Key Findings:
- No concomitant exposure to other TMA-causing drugs (gemcitabine, anti-VEGF agents, mTOR inhibitors)
- Work-up for secondary causes of TMA negative
- Cessation of PLD led to improvement or stabilization
Mechanism: The prolonged half-life of PLD and its accumulation in vascular endothelium likely contribute to endothelial injury, triggering TMA .
2.3.4 Regulatory Action
PRAC recommended that MAHs of pegylated liposomal doxorubicin submit a variation within two months to amend product information.
SmPC Section 4.8:
“Renal and urinary disorders: Renal-limited thrombotic microangiopathy: frequency – not known”
Package Leaflet:
“Not known (frequency cannot be estimated from the available data): clogging of very small blood vessels in the kidneys (renal-limited thrombotic microangiopathy)”
2.3.5 Clinical Implications
| Implication | Action |
|---|---|
| Monitoring | Monitor renal function regularly in patients receiving PLD |
| Awareness | Consider renal-limited TMA in patients who develop unexplained renal impairment, even without systemic signs |
| Differential diagnosis | Rule out other causes of renal dysfunction (dehydration, infection, other nephrotoxins) |
| Investigation | If suspected, consider urinalysis, LDH, haptoglobin, platelet count, peripheral smear (schistocytes), and possibly kidney biopsy |
| Management | Drug discontinuation is the first step; supportive care; may require specific treatment depending on severity |
| Reporting | Report any suspected cases to pharmacovigilance authorities |
3. Recommendations for Submission of Supplementary Information
3.1 Atropine (Eyedrops) – Strabismus
Signal EPITT No: 20244
Action: Assess in the ongoing PSUR (submission by 12 March 2026)
MAH: Santen Oy
3.1.1 Background
Atropine eye drops are used to slow the progression of myopia in paediatric patients. Atropine is a muscarinic antagonist that induces cycloplegia (paralysis of accommodation) and mydriasis (pupil dilation) .
3.1.2 The Signal: Strabismus
Strabismus (misalignment of the eyes) has been reported as a potential adverse effect. The current atropine data sheet lists “ocular disorders” including conjunctivitis, hyperaemia, eye oedema, and secretion, but does not specifically list strabismus .
3.1.3 Clinical Considerations
3.2 Darolutamide – Angioedema
Signal EPITT No: 20237
Action: Supplementary information requested (submission by 8 April 2026)
MAH: Bayer AG
3.2.1 Background
Darolutamide is an androgen receptor pathway inhibitor (ARPI) used in the treatment of non-metastatic castration-resistant prostate cancer. It has a favourable cardiovascular safety profile compared to other ARPIs.
3.2.2 The Signal: Angioedema
Angioedema is a potentially life-threatening condition involving rapid swelling of the deeper layers of the skin, often affecting the face, lips, tongue, and upper airways.
Mechanism: ARPIs have been associated with various cardiovascular and hypersensitivity reactions. A recent case report documented severe cardiac events including cardiomyopathy and arrhythmias in a patient on darolutamide , though angioedema represents a distinct hypersensitivity mechanism.
3.3 Oxacillin – DRESS Syndrome
Signal EPITT No: 20223
Action: Supplementary information requested (submission by 8 April 2026)
MAH: Laboratoires Delbert
3.3.1 What is DRESS Syndrome?
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a rare but severe and potentially life-threatening hypersensitivity reaction with significant morbidity and mortality .
Diagnostic Criteria (RegiSCAR):
| Feature | Description |
|---|---|
| Hospitalization | Required for management |
| Fever | >38°C |
| Lymphadenopathy | Enlarged lymph nodes |
| Eosinophilia | >700/μL or >10% |
| Atypical lymphocytes | Present |
| Skin rash | Extensive, often morbiliform |
| Internal organ involvement | Hepatitis, nephritis, pneumonitis, myocarditis |
| Resolution | Prolonged over weeks to months |
3.3.2 Clinical Case Example
A 2021 case report described DRESS syndrome in a 55-year-old male following oxacillin therapy for methicillin-sensitive Staphylococcus aureus bacteremia . The patient developed:
- Generalized pruritic rash with fever 3 weeks after starting oxacillin
- Blanchable maculopapular rash involving face, trunk, and extremities
- Palpable cervical and inguinal lymphadenopathy
- Atypical lymphocytosis, eosinophilia, neutrophilia
- Elevated serum transaminases
Management: Oxacillin was discontinued and switched to cefazolin; diphenhydramine administered; fever resolved but rash persisted .
3.3.3 Clinical Implications
3.4 Vortioxetine – Acute Pancreatitis
Signal EPITT No: 20234
Action: Supplementary information requested (submission by 8 April 2026)
MAH: H. Lundbeck A/S
3.4.1 Background
Vortioxetine is a multimodal antidepressant used for the treatment of major depressive disorder. A decade-long pharmacovigilance study based on FAERS data identified multiple safety signals .
3.4.2 Identified Signals
The FAERS analysis revealed:
3.4.3 Acute Pancreatitis Signal
Acute pancreatitis represents a new safety signal requiring further investigation. Pancreatitis is a serious condition with potential for significant morbidity, including pancreatic necrosis, pseudocyst formation, and systemic inflammatory response.
3.5 X-Ray Contrast Agents – Fixed Drug Eruption
Signal EPITT No: 20229
Action: Supplementary information requested (submission by 8 April 2026)
MAHs: Bracco Imaging, GE Healthcare, Bayer, Guerbet
3.5.1 Agents Under Review
The signal encompasses multiple iodinated non-ionic X-ray contrast media:
- Iobitridol
- Iodixanol
- Iohexol
- Iomeprol
- Iopamidol
- Iopromide
- Ioversol
- Ioxitalamic acid
3.5.2 What is Fixed Drug Eruption?
Fixed drug eruption (FDE) is a distinctive cutaneous adverse reaction characterized by recurrent lesions at the same anatomical site(s) each time the offending drug is administered.
Clinical Features:
- Well-demarcated, round or oval patches
- Typically erythematous, may be bullous
- Lesions appear within hours of drug exposure
- Recur at same sites (most commonly genitalia, lips, hands, feet)
- May leave hyperpigmentation on resolution
3.5.3 Evidence for Contrast-Induced FDE
Literature reports document fixed drug eruption following iodinated contrast media administration. Watanabe and colleagues reported multiple fixed drug eruption caused by iomeprol . Other reports implicate iohexol, iopamidol, and other non-ionic agents .
Mechanism: T-cell mediated delayed hypersensitivity; skin-resident memory T cells play a crucial role .
Diagnostic Approach:
- Skin patch testing may have low negative predictive value
- Lymphocyte transformation tests can support diagnosis
- Rechallenge is diagnostic but carries risk
3.5.4 Clinical Implications
| Implication | Action |
|---|---|
| History taking | Ask about prior contrast reactions before administration |
| Site identification | Document location of previous reactions |
| Prevention | Avoid re-exposure to same contrast agent; consider alternative if clinically necessary |
| Management | Treat with topical or systemic corticosteroids as needed |
3.6 Zolbetuximab – Protein-Losing Gastroenteropathy
Signal EPITT No: 20236
Action: Supplementary information requested (submission by 8 April 2026)
MAH: Astellas Pharma Europe B.V.
3.6.1 Background
Zolbetuximab is a monoclonal antibody targeting Claudin 18.2, approved for the treatment of advanced gastric cancer. Its anticancer effects occur through antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
3.6.2 The Signal: Protein-Losing Gastroenteropathy
A 2025 case report documented zolbetuximab-induced protein-losing gastroenteropathy in a patient with advanced gastric cancer .
Key Findings:
- Patient developed hypoalbuminemia and edema during treatment
- Protein leakage from the upper gastrointestinal tract confirmed via protein leakage scintigraphy
- Edema and hypoalbuminemia are known adverse events, but underlying mechanism was previously unclear
Mechanistic Insight: This case provides evidence that protein-losing gastroenteropathy—loss of plasma proteins into the gastrointestinal tract—is responsible for zolbetuximab-associated hypoalbuminemia and edema .
3.6.3 Clinical Implications
| Implication | Action |
|---|---|
| Monitoring | Monitor serum albumin levels during zolbetuximab therapy |
| Symptom assessment | Assess for edema, weight gain, dyspnoea |
| Diagnosis | If unexplained hypoalbuminemia occurs, consider protein-losing gastroenteropathy and evaluate with fecal alpha-1 antitrypsin or scintigraphy |
| Management | May require nutritional support, albumin infusion, or treatment modification |
3.7 Zuranolone – Suicidal Ideation
Signal EPITT No: 20232
Action: Assess in the next PSUR (submission by 14 April 2026)
MAH: Biogen Netherlands B.V.
3.7.1 Background
Zuranolone is a neuroactive steroid and positive allosteric modulator of GABA-A receptors, approved for the treatment of postpartum depression (PPD).
3.7.2 The Signal: Suicidal Ideation
Suicidal ideation is a critical safety concern for any antidepressant, particularly in populations already at risk. The post-partum period carries inherent risk for mood disturbances, making this signal particularly important.
Clinical Context:
- All antidepressants carry a boxed warning for increased risk of suicidal thinking and behavior in children, adolescents, and young adults
- For PPD treatment, the balance of benefits against potential risks requires careful assessment
- The signal requires evaluation of:
- Temporal association with drug exposure
- Dose relationship
- Dechallenge/rechallenge information
- Underlying disease contribution
4. Other Recommendations
4.1 Erdafitinib – Musculoskeletal Disorders in Adults
Action: Assess musculoskeletal disorders in adult patients in the next PSUR (submission by 20 June 2026)
4.2 Pemetrexed – Lupus Erythematosus
Signal EPITT No: 20185
Action: Monitor in PSUR
MAHs: All MAHs of pemetrexed-containing products with obligation to submit PSURs
Background: Pemetrexed is an antifolate antineoplastic agent used in the treatment of mesothelioma and non-small cell lung cancer. Drug-induced lupus erythematosus is a known but rare adverse effect, requiring continued monitoring.
5. Practical Summary for Healthcare Professionals
5.1 Quick Reference Table
| Drug | Signal | Clinical Presentation | Action Required |
|---|---|---|---|
| Cefazolin | Kounis syndrome | Chest pain during/after allergic reaction; ECG changes; elevated cardiac enzymes | Stop drug; manage as both allergy and ACS; report |
| Erdafitinib | Growth acceleration, epiphysiolysis | Accelerated growth; hip/knee pain; limp in children | Avoid off-label paediatric use; monitor exposed children |
| Pegylated liposomal doxorubicin | Renal-limited TMA | Rising creatinine, proteinuria; may lack systemic TMA signs | Monitor renal function; consider biopsy; discontinue if suspected |
| Atropine (eye drops) | Strabismus | Eye misalignment in children | Monitor paediatric patients; report cases |
| Darolutamide | Angioedema | Facial, lip, tongue swelling; airway compromise | Recognize early; discontinue if suspected |
| Oxacillin | DRESS syndrome | Rash, fever, eosinophilia, organ involvement 3+ weeks after start | Discontinue; supportive care; report |
| Vortioxetine | Acute pancreatitis | Abdominal pain, elevated lipase/amylase | Consider in differential; monitor |
| X-ray contrast agents | Fixed drug eruption | Recurrent lesions at same sites; genital area common | Document prior reactions; avoid re-exposure |
| Zolbetuximab | Protein-losing gastroenteropathy | Edema, hypoalbuminemia; protein leakage into GI tract | Monitor albumin; consider diagnostic evaluation |
| Zuranolone | Suicidal ideation | New or worsening suicidal thoughts | Monitor closely; assess benefit-risk |
6. Conclusion
The January 2026 PRAC meeting highlights the dynamic nature of medication safety and the critical role of pharmacovigilance in protecting patient health. The signals reviewed span diverse therapeutic areas and adverse reaction types:
- Cardiovascular: Kounis syndrome with cefazolin
- Paediatric: Growth effects with erdafitinib
- Renal: Thrombotic microangiopathy with PLD
- Dermatologic: DRESS syndrome with oxacillin, fixed drug eruption with contrast agents
- Gastrointestinal: Acute pancreatitis with vortioxetine, protein-losing gastroenteropathy with zolbetuximab
- Psychiatric: Suicidal ideation with zuranolone
- Ophthalmic: Strabismus with atropine
- Hypersensitivity: Angioedema with darolutamide
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.
