Based on EMA Pharmacovigilance Risk Assessment Committee (PRAC) Recommendations on Signals – Adopted 12–15 January 2026
February 2026
The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) meets regularly to evaluate safety signals for medicinal products and recommend updates to product information. At its January 2026 meeting, PRAC adopted important new safety information concerning three distinct medicinal products: cefazolin (and cefazolin with lidocaine), erdatinib, and pegylated liposomal doxorubicin.
This article provides a comprehensive medical analysis of these safety signals, including the clinical presentation, pathophysiology, patient impact, and implications for healthcare professionals. We examine each signal in detail, explaining the scientific basis for the regulatory actions and offering practical guidance for clinical practice.
Section 1: Cefazolin and Kounis Syndrome
1.1 Background: Cefazolin
Cefazolin is a first-generation cephalosporin antibiotic widely used for:
- Surgical prophylaxis
- Treatment of respiratory tract infections
- Skin and soft tissue infections
- Bone and joint infections
- Endocarditis
- Septicaemia
It is often administered in combination with lidocaine hydrochloride for intramuscular injection to reduce injection site pain.
1.2 The Safety Signal: Kounis Syndrome
PRAC identified a safety signal for Kounis syndrome associated with cefazolin use. This represents an important addition to the product information, as Kounis syndrome is a potentially life-threatening condition that may be under-recognised in clinical practice.
1.2.1 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 involves:
| Component | Description |
|---|---|
| Pathophysiology | Allergic or hypersensitivity reaction triggers mast cell degranulation, releasing inflammatory mediators (histamine, leukotrienes, prostaglandins) |
| Mechanism | Mediators cause coronary artery vasospasm, plaque erosion/rupture, or stent thrombosis |
| Result | Reduced coronary blood flow, potentially leading to myocardial infarction |
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.
1.2.2 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 |
1.2.3 Clinical Presentation
Patients with Kounis syndrome may present with:
| Symptoms | Signs |
|---|---|
| Chest pain (often acute onset) | ST-segment changes on ECG (elevation or depression) |
| Dyspnoea | Elevated cardiac enzymes (troponin, CK-MB) |
| Palpitations | Hypotension |
| Diaphoresis | Tachycardia or bradycardia |
| Pruritus, urticaria (concurrent allergic symptoms) | Wheezing, angioedema |
| Nausea, vomiting | Syncope |
Critical Distinction: Unlike typical myocardial infarction, Kounis syndrome occurs in the context of an allergic reaction. Patients may present with simultaneous features of hypersensitivity and acute coronary syndrome.
1.3 Regulatory Action
PRAC recommended the following additions to cefazolin product information:
Summary of Product Characteristics (SmPC)
Section 4.4 – Special warnings and precautions for use (Hypersensitivity):
“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.”
Section 4.8 – Undesirable effects (Cardiac disorders):
“Kounis syndrome” with frequency “Not known”
Package Leaflet
Section 2 – What you need to know before you take:
“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.”
Section 4 – Possible side effects:
“Not known (frequency cannot be estimated from the available data): Chest pain, which can be a sign of a potentially serious allergic reaction called Kounis syndrome.”
1.4 Clinical Implications for Healthcare Professionals
| Implication | Action |
|---|---|
| Awareness | Recognise that chest pain during or after cefazolin administration may represent Kounis syndrome, not simply a “reaction” |
| Patient education | Counsel patients to seek immediate medical attention if they experience chest pain with signs of allergy |
| 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 |
Section 2: Erdatinib – Growth Effects in Paediatric Patients
2.1 Background: Erdatinib
Erdatinib is a kinase inhibitor indicated for the treatment of urothelial carcinoma in adults. It is not authorised for use in paediatric patients, and there is no relevant use in children for this indication.
2.2 The Safety Signal: Growth Acceleration and Epiphysiolysis
PRAC identified a safety signal concerning growth acceleration and epiphysiolysis of the femoral head in paediatric patients exposed to erdatinib. These effects were observed:
- In clinical trials conducted outside the authorised indication
- In off-label post-marketing use in patients under 18 years of age
2.2.1 What is Epiphysiolysis of the Femoral Head?
| Term | Definition |
|---|---|
| Epiphysiolysis | Separation or slippage of the epiphysis (the growing end of a bone) from the main bone shaft |
| Femoral head | The “ball” part of the hip joint that fits into the hip socket |
| Slipped Capital Femoral Epiphysis (SCFE) | The clinical condition where the femoral head slips relative to the femoral neck through the growth plate |
Pathophysiology:
- The growth plate (physis) is the weakest part of the developing skeleton
- Hormonal or drug influences can weaken the growth plate or accelerate growth, making slippage more likely
- This is particularly relevant during periods of rapid growth (adolescence)
2.2.2 Clinical Presentation of Epiphysiolysis
| Feature | Description |
|---|---|
| Pain | Hip, groin, thigh, or knee pain (referred pain is common) |
| Limp | Antalgic gait (painful limp) or Trendelenburg gait |
| Limited movement | Particularly internal rotation of the hip |
| Acute vs. chronic | Can present acutely (severe pain, inability to bear weight) or chronically (gradual onset, mild symptoms) |
| Bilateral | Occurs bilaterally in up to 60% of cases |
Growth Acceleration: Premature or excessive growth may place additional stress on the growth plates, potentially contributing to epiphysiolysis.
2.3 Regulatory Action
PRAC recommended the following additions to erdatinib product information:
Summary of Product Characteristics (SmPC)
Section 4.2 – Posology and method of administration (Paediatric population):
“There is no relevant use of erdatinib in the paediatric population for the treatment of urothelial carcinoma. The safety and efficacy of erdatinib in paediatric patients (< 18 years of age) have not been established. Currently available safety data are described in section 4.8.”
Section 4.8 – Undesirable effects (under ‘Description of selected adverse reactions’):
*”Paediatric population: Growth acceleration and epiphysiolysis of the femoral head have been reported in paediatric patients (<18 years of age) receiving erdatinib in clinical trials outside of the authorised indication and off label in the post-marketing setting.”*
Section 5.1 – Pharmacodynamic properties (Paediatric population):
“The European Medicines Agency has waived the obligation to submit the results of studies with erdatinib in all subsets of the paediatric population in urothelial carcinoma (see sections 4.2 and 4.8 for information on paediatric use).”
Package Leaflet
Section 4 – Possible side effects:
“Additional side effects in children and adolescents: 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.”
2.4 Clinical Implications
| Implication | Action |
|---|---|
| Off-label use warning | Erdatinib should not be used in paediatric patients except in approved clinical trials |
| Monitoring | If a paediatric patient has been exposed (accidentally or off-label), 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 |
| Reporting | Report any suspected adverse reactions in paediatric patients exposed to erdatinib |
Section 3: Pegylated Liposomal Doxorubicin – Renal-Limited Thrombotic Microangiopathy
3.1 Background: Pegylated Liposomal Doxorubicin
Doxorubicin is an anthracycline antibiotic used in cancer chemotherapy. Pegylated liposomal doxorubicin is a formulation where the drug is encapsulated in liposomes coated with polyethylene glycol (PEG), which:
- Prolongs circulation time
- Alters biodistribution
- Reduces cardiotoxicity compared to conventional doxorubicin
Indications include:
- Ovarian cancer
- Multiple myeloma (in combination with bortezomib)
- AIDS-related Kaposi’s sarcoma
- Breast cancer (in some countries)
3.2 The Safety Signal: Renal-Limited Thrombotic Microangiopathy
PRAC identified a safety signal for renal-limited thrombotic microangiopathy (TMA) associated with pegylated liposomal doxorubicin.
3.2.1 What is Thrombotic Microangiopathy?
Thrombotic microangiopathy is a pathological condition characterised by:
| Feature | Description |
|---|---|
| Microvascular thrombosis | Formation of platelet-rich thrombi in small blood vessels |
| Microangiopathic haemolytic anaemia | Red blood cell fragmentation as they pass through partially occluded vessels |
| Thrombocytopenia | Platelet consumption in thrombi |
| Organ damage | Ischaemic injury to affected organs (most commonly kidneys, brain) |
Classic TMA syndromes include:
- Thrombotic thrombocytopenic purpura (TTP)
- Haemolytic uraemic syndrome (HUS)
- Drug-induced TMA
3.2.2 Renal-Limited TMA: A Distinct Entity
The term “renal-limited thrombotic microangiopathy” refers to TMA that is confined to the kidneys, without the characteristic systemic features:
| Feature | Classic Systemic TMA | Renal-Limited TMA |
|---|---|---|
| Kidney involvement | Present | Present |
| Neurological symptoms | Often present (confusion, seizures) | 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 |
Why this matters: Renal-limited TMA can be easily missed because patients lack the classic systemic signs. It may present simply as unexplained renal dysfunction.
3.2.3 Pathophysiology of Drug-Induced TMA
Drug-induced TMA can occur through several mechanisms:
| Mechanism | Description |
|---|---|
| Direct endothelial toxicity | Drug damages vascular endothelial cells directly |
| Immune-mediated | Drug induces antibodies that activate platelets or damage endothelium |
| ADAMTS13 inhibition | Reduced activity of the enzyme that cleaves von Willebrand factor |
| Complement activation | Uncontrolled activation of the alternative complement pathway |
For doxorubicin and related compounds, endothelial injury is a well-recognised effect, which may explain the association with TMA.
3.3 Regulatory Action
PRAC recommended the following additions to pegylated liposomal doxorubicin product information:
Summary of Product Characteristics (SmPC)
Section 4.8 – Undesirable effects (Renal and urinary disorders):
“Renal-limited thrombotic microangiopathy: frequency – not known”
Package Leaflet
Section 4 – Possible side effects:
“Not known (frequency cannot be estimated from the available data): clogging of very small blood vessels in the kidneys (renal-limited thrombotic microangiopathy)”
3.4 Clinical Implications
| Implication | Action |
|---|---|
| Monitoring | Monitor renal function regularly in patients receiving pegylated liposomal doxorubicin |
| 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 (proteinuria, haematuria), 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 |
Section 4: Practical Summary for Healthcare Professionals
4.1 Quick Reference Table
| Drug | New Safety Information | Clinical Action |
|---|---|---|
| Cefazolin | Kounis syndrome (allergic acute coronary syndrome) | Recognise chest pain during allergic reaction as potential cardiac event; stop drug immediately; manage as both allergy and ACS |
| Erdatinib | Growth acceleration and femoral head epiphysiolysis in children | Avoid off-label paediatric use; monitor exposed children for hip/knee pain or limp; refer urgently if suspected |
| Pegylated liposomal doxorubicin | Renal-limited thrombotic microangiopathy | Monitor renal function; consider TMA in unexplained renal impairment even without systemic features |
4.2 Patient Communication Points
| Drug | Key Message for Patients |
|---|---|
| Cefazolin | “If you develop chest pain along with signs of an allergic reaction (breathing problems, rash), stop the medicine and seek emergency care immediately.” |
| Erdatinib | “This medicine is not for use in children. If a child accidentally takes it, watch for hip or knee pain or limping, and tell your doctor right away.” |
| Pegylated liposomal doxorubicin | “This medicine can affect kidney function. Your doctor will monitor your blood tests. Report any changes in urination or swelling.” |
Section 5: The Pharmacovigilance Perspective
5.1 Signal Detection and Evaluation
These three safety signals illustrate the importance of:
| Signal Type | Detection Method | Evaluation |
|---|---|---|
| Kounis syndrome (cefazolin) | Spontaneous reporting; literature review | Clinical assessment of case series; understanding of pathophysiology |
| Paediatric growth effects (erdatinib) | Clinical trials (off-indication); off-label use reports | Analysis of trial data; post-marketing surveillance |
| Renal-limited TMA (doxorubicin) | Spontaneous reporting; literature | Pathophysiological plausibility; case series analysis |
5.2 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
Remember: If you suspect an adverse reaction, report it. Your report could be the one that helps identify a new safety signal and protects future patients.
Conclusion: Protecting Patients Through Vigilance
The January 2026 PRAC recommendations highlight the dynamic nature of medication safety. Three distinct safety signals—Kounis syndrome with cefazolin, growth effects with erdatinib, and renal-limited TMA with pegylated liposomal doxorubicin—demonstrate the diverse ways in which adverse reactions can manifest.
For healthcare professionals, these updates serve as important reminders:
- Cefazolin: Allergic reactions can extend beyond rash and anaphylaxis to include cardiac manifestations. Chest pain in the context of antibiotic administration requires urgent evaluation.
- Erdatinib: Off-label use in vulnerable populations (children) can uncover unexpected safety issues. Growth and development must be monitored when children receive medications not studied in paediatric populations.
- Pegylated liposomal doxorubicin: Organ-limited adverse reactions can be subtle. Renal-limited TMA may present without systemic signs, requiring vigilance in monitoring and diagnosis.
By staying informed of regulatory updates, maintaining clinical vigilance, and reporting suspected adverse reactions, healthcare professionals contribute to the continuous improvement of medication safety for patients across Europe and beyond.
