The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency met on 4–7 May 2026 and adopted important recommendations for multiple safety signals. This article provides a comprehensive medical analysis of the signals reviewed, including a new product information update for pancreatin-containing products regarding hepatitis E virus (HEV) transmission, supplementary information requests for amoxicillin-associated encephalopathy, dapagliflozin and lichen sclerosus, semaglutide and peripheral neuropathies, semaglutide and gastrointestinal volvulus, ixekizumab and Behçet’s syndrome, tocilizumab and cutaneous vasculitis, and a no-action decision for benzodiazepines and miscarriage.
For each signal, we explore the clinical presentation, pathophysiology, evidence base, 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 assessing and monitoring safety issues for human medicines. At its meeting of 4–7 May 2026, PRAC evaluated multiple safety signals and adopted recommendations ranging from product information updates to requests for supplementary information and no-action decisions.
2. Signal 1: Pancreatin – Infection Due to Viral Transmission (Hepatitis E Virus)
Signal EPITT No: 20205
PRAC Rapporteur: Dennis Lex
Authorisation Procedure: Non-centralised
Action: Product information update (variation within 2 months)
2.1 Background: Pancreatin and Its Therapeutic Use
Pancreatin is a combination of digestive enzymes (lipase, protease, and amylase) derived from porcine (pig) pancreatic tissue. It is indicated for:
| Indication | Description |
|---|---|
| Exocrine pancreatic insufficiency (EPI) | Commonly associated with cystic fibrosis, chronic pancreatitis, pancreatic surgery, and pancreatic cancer |
| Pancreatectomy | Following surgical removal of all or part of the pancreas |
| Chronic pancreatitis | Long-standing inflammation leading to impaired enzyme production |
Pancreatin replacement therapy is essential for patients with EPI to maintain adequate nutrition and prevent malabsorption-related complications.
2.2 The Signal: Hepatitis E Virus (HEV) Transmission
PRAC identified a safety signal concerning hepatitis E virus (HEV) transmission via pancreatin-containing medicinal products derived from porcine sources.
2.2.1 What is Hepatitis E Virus?
Hepatitis E virus is a single-stranded RNA virus belonging to the family Hepeviridae. It is transmitted primarily through the faecal-oral route, often via contaminated water in endemic areas (particularly South Asia, Africa, and Latin America).
However, HEV can also be transmitted through consumption of undercooked pork and wild game meat, and through blood transfusion and organ transplantation.
| Feature | Description |
|---|---|
| Genotypes | 7 genotypes; genotypes 1 and 2 infect humans only; genotypes 3 and 4 are zoonotic (pigs, wild boar, deer) |
| Transmission | Faecal-oral, zoonotic (pork products), blood transfusion, vertical transmission, and organ transplantation |
| Clinical presentation | Acute hepatitis: fatigue, jaundice, dark urine, abdominal pain, nausea, vomiting; usually self-limiting |
| High-risk groups | Pregnant women (particularly third trimester—high mortality), immunosuppressed patients (chronic infection risk) |
| Immunosuppressed patients | Can develop chronic hepatitis E with persistent viraemia and progressive liver fibrosis |
| Diagnosis | HEV RNA PCR (serum/stool); anti-HEV IgM/IgG antibodies |
| Treatment | Supportive care; ribavirin for chronic infection in immunosuppressed patients |
2.2.2 The Evidence: HEV Seroprevalence in Cystic Fibrosis Patients
A cross-sectional study suggested a higher HEV seroprevalence in patients with cystic fibrosis using pancreatic enzyme replacement therapy than in individuals who do not use pancreatin. However, the study is subject to important limitations, including:
| Limitation | Description |
|---|---|
| Timing uncertainty | Uncertainty regarding the timing of past infection (could have occurred before or after starting therapy) |
| Other sources | Potential for other sources of HEV (e.g., dietary exposure to pork products) |
| Confounding | Cystic fibrosis patients may have other risk factors for HEV infection |
Despite these limitations, PRAC concluded that a precautionary approach was warranted, particularly for immunosuppressed patients receiving high daily doses of pancreatin.
2.2.3 Manufacturing and Viral Safety
Despite measures taken during manufacturing to reduce the risk (including sourcing from HEV-free herds, testing, and viral inactivation steps), the presence of HEV in medicinal products containing pancreas powder extracts of animal (porcine) origin is possible.
2.3 Regulatory Action
PRAC recommended that all Marketing Authorisation Holders (MAHs) of pancreatin-containing medicinal products submit a variation within two months to amend product information.
Summary of Product Characteristics (SmPC) – Section 4.4
“Despite measures taken during manufacturing to reduce the risk, the presence of hepatitis E virus (HEV) in medicinal products containing pancreas powder extracts of animal (porcine) origin is possible. A cross-sectional study has suggested a higher HEV seroprevalence in patients with cystic fibrosis using pancreatic enzyme replacement therapy than in individuals who do not use pancreatin. This study is subject to important limitations including uncertainty with regards to the timing of past infection, as well as the potential for other sources of HEV. As a precaution, immunosuppressed patients receiving high daily dosing should be advised about symptoms of viral hepatitis and to seek medical attention if such symptoms occur.”
Package Leaflet – Section 2
“This medicine is of animal (pig) origin. Although steps are taken during manufacturing to reduce the risk, the presence of hepatitis E virus in this medicine is possible. Hepatitis E is a virus that can be present in pigs, which can be spread to humans and may cause infection of the liver. A study has suggested that people with cystic fibrosis who have taken this medicine may be more likely to have had hepatitis E in the past. However, this study has important limitations. For example, it is unclear when the past infection happened or what the source of the infection was.”
2.4 Clinical Implications for Healthcare Professionals
| Implication | Action |
|---|---|
| Immunosuppressed patients | Advise patients receiving high daily dosing of pancreatin about symptoms of viral hepatitis (fatigue, jaundice, dark urine, abdominal pain, nausea) and to seek medical attention if such symptoms occur |
| Risk communication | Counsel patients that HEV infection is a potential risk, but the absolute risk is low and the benefits of pancreatin replacement therapy outweigh the risks |
| Diagnostic awareness | Consider HEV infection in patients with unexplained hepatitis, particularly those on long-term pancreatin therapy |
| Reporting | Report any suspected cases of HEV infection in patients taking pancreatin to national pharmacovigilance centres |
2.5 Additional Actions
PRAC also recommended that all MAHs of pancreatin-containing products review their quality process and submit the outcome of the assessment to the relevant national competent authorities.
3. Signal 2: Amoxicillin and Amoxicillin/Clavulanic Acid – Encephalopathy
Signal EPITT No: 20264
PRAC Rapporteurs: Jan Neuhauser (AT) – Amoxicillin; Dennis Lex (DE) – Amoxicillin/Clavulanic Acid
Action: Assess in the next PSUR (submission by 5 June 2027)
3.1 Background
Amoxicillin is a broad-spectrum penicillin antibiotic widely used for respiratory, urinary, and skin infections. Amoxicillin/clavulanic acid (co-amoxiclav) combines amoxicillin with a beta-lactamase inhibitor, extending its spectrum to cover beta-lactamase-producing organisms.
3.2 The Signal: Encephalopathy
PRAC identified a signal for encephalopathy associated with both amoxicillin and amoxicillin/clavulanic acid.
3.2.1 What is Encephalopathy?
Encephalopathy is a general term for diffuse brain dysfunction that alters brain function or structure. It can present with:
| Feature | Description |
|---|---|
| Altered mental status | Confusion, drowsiness, disorientation, delirium |
| Cognitive impairment | Memory problems, reduced attention, poor judgment |
| Behavioural changes | Agitation, personality changes, psychosis |
| Neurological symptoms | Seizures, myoclonus, tremor, ataxia |
| Motor dysfunction | Weakness, incoordination, speech difficulties |
| Autonomic dysfunction | Fever, blood pressure instability |
Types of encephalopathy relevant to drug reactions:
- Metabolic encephalopathy: Drug-induced metabolic disturbances (e.g., electrolyte imbalances, hepatic encephalopathy, uraemic encephalopathy)
- Toxic encephalopathy: Direct neurotoxic effect of the drug or its metabolites
- Immune-mediated encephalopathy: Drug-induced autoimmune encephalitis
- Posterior Reversible Encephalopathy Syndrome (PRES): Vasogenic oedema with characteristic MRI findings
3.2.2 Proposed Mechanisms for Beta-Lactam-Associated Encephalopathy
| Mechanism | Description |
|---|---|
| GABA-A receptor antagonism | Beta-lactam antibiotics can inhibit GABA-A receptors, reducing inhibitory neurotransmission and increasing seizure risk |
| Cytokine-mediated neuroinflammation | Drug-induced immune activation may cause neuroinflammation |
| Direct neurotoxicity | Accumulation of drug or metabolites in the central nervous system, particularly in renal impairment |
| Cerebral vasospasm | Rarely, drug-induced vasospasm can cause cerebral ischaemia and encephalopathy |
Risk Factors for Beta-Lactam-Associated Encephalopathy:
| Risk Factor | Explanation |
|---|---|
| Renal impairment | Reduced drug clearance leads to accumulation; dose adjustment is essential |
| Advanced age | Age-related changes in pharmacokinetics and increased susceptibility |
| High doses | Particularly with intravenous administration |
| Pre-existing CNS disease | Epilepsy, stroke, dementia, Parkinson’s disease |
| Concurrent neurotoxic drugs | Aminoglycosides, metronidazole, quinolones |
3.3 Evidence from EudraVigilance and Literature
A systematic review of beta-lactam-induced encephalopathy identified:
- Reports of encephalopathy associated with amoxicillin and amoxicillin/clavulanic acid
- Cases often involved patients with renal impairment receiving high doses
- Common presentations include confusion, myoclonus, seizures, and altered consciousness
- Most patients recovered after drug discontinuation or dose adjustment
A 2018 case report described a 79-year-old woman with renal failure who developed encephalopathy after amoxicillin/clavulanic acid treatment, with symptoms including confusion, agitation, myoclonus, and hallucinations. Complete recovery occurred after drug discontinuation.
3.4 Regulatory Action
PRAC requested that MAHs assess the signal in the next Periodic Safety Update Report (PSUR) with submission by 5 June 2027. This will allow:
- Cumulative case review (spontaneous reports, literature, clinical trials)
- Detailed case-by-case evaluation (causality, risk factors, outcomes)
- Analysis of incidence rates (exposure-adjusted)
- Proposed updates to product information if warranted
3.5 Clinical Implications for Healthcare Professionals
| Implication | Action |
|---|---|
| Renal function assessment | Before prescribing amoxicillin or co-amoxiclav, assess renal function and adjust dose accordingly (especially in elderly patients) |
| Symptom recognition | Maintain high index of suspicion for encephalopathy in patients on beta-lactam antibiotics presenting with confusion, myoclonus, seizures, or altered consciousness |
| Differential diagnosis | Consider drug-induced encephalopathy in the differential of acute confusion in hospitalised patients |
| Management | If encephalopathy is suspected, consider discontinuing the antibiotic (or reducing the dose) and providing supportive care |
| Reporting | Report any suspected cases of encephalopathy to national pharmacovigilance centres |
4. Signal 3: Dapagliflozin (and Combinations) – Lichen Sclerosus
Signal EPITT No: 20259
PRAC Rapporteur: Mari Thörn (SE)
Action: Supplementary information requested (submission by 29 July 2026)
4.1 Background
Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor indicated for:
- Type 2 diabetes mellitus
- Heart failure (reduced ejection fraction)
- Chronic kidney disease
It is available as monotherapy and in fixed-dose combinations with metformin, saxagliptin, and sitagliptin.
4.2 The Signal: Lichen Sclerosus
PRAC identified a signal for lichen sclerosus associated with dapagliflozin-containing products.
4.2.1 What is Lichen Sclerosus?
Lichen sclerosus is a chronic inflammatory skin condition of unknown aetiology that primarily affects the anogenital area.
| Feature | Description |
|---|---|
| Prevalence | Estimated 1 in 300 to 1 in 1,000; more common in women (female-to-male ratio up to 10:1) |
| Age distribution | Bimodal: prepubertal children and postmenopausal women (peak age 40-60) |
| Clinical presentation | White, atrophic, wrinkled plaques; pruritus (intense); pain, burning; dyspareunia; dysuria; bleeding, erosions, fissures |
| Complications | Scarring, phimosis (men), vaginal introital stenosis (women), increased risk of squamous cell carcinoma (2-5%) |
| Diagnosis | Clinical examination; skin biopsy (definitive) |
| Treatment | Potent topical corticosteroids (clobetasol propionate); calcineurin inhibitors (tacrolimus, pimecrolimus); surgery for scarring |
4.2.2 Pathophysiology
The exact aetiology of lichen sclerosus is unknown, but proposed mechanisms include:
| Mechanism | Description |
|---|---|
| Autoimmune | Strong association with other autoimmune diseases (thyroid disease, alopecia areata, vitiligo, pernicious anaemia) |
| Genetic | HLA associations (HLA-DQ7, HLA-DR12) |
| Hormonal | Androgen deficiency theory (controversial) |
| Infectious | Borrelia burgdorferi association (controversial) |
| Drug-induced | SGLT2 inhibitors are a newly identified potential trigger |
4.2.3 Drug-Induced Lichen Sclerosus and SGLT2 Inhibitors
The mechanism by which SGLT2 inhibitors might trigger lichen sclerosus is not fully understood. Proposed mechanisms include:
| Mechanism | Description |
|---|---|
| Immune modulation | SGLT2 inhibitors may alter immune regulation in susceptible individuals |
| Local tissue effects | Changes in glucose metabolism in skin and genital tissues may alter the local microenvironment |
| Inflammatory response | Drug-induced inflammation in genetically predisposed individuals |
4.3 Regulatory Action
PRAC requested supplementary information from the MAH (AstraZeneca AB) by 29 July 2026, including:
- Cumulative case review (spontaneous reports, literature, clinical trials)
- Detailed case-by-case evaluation (causality, risk factors, outcomes)
- Assessment of incidence and temporal relationship
- Proposed risk minimisation measures if warranted
4.4 Clinical Implications for Healthcare Professionals
| Implication | Action |
|---|---|
| Awareness | Be aware of the potential for lichen sclerosus in patients on SGLT2 inhibitors presenting with anogenital itching or skin changes |
| Differential diagnosis | Consider lichen sclerosus in the differential of genital itching or skin lesions in patients on dapagliflozin (distinguish from fungal infections, which are more common) |
| Referral | Refer suspected cases to dermatology for confirmation (skin biopsy may be needed) |
| Management | If lichen sclerosus is diagnosed, consider the benefit-risk balance of continuing dapagliflozin; topical corticosteroids are the mainstay of treatment |
| Patient education | Counsel patients to report any new anogenital itching, pain, or skin changes |
| Reporting | Report any suspected cases to national pharmacovigilance centres |
5. Signal 4: Semaglutide and Insulin Icodec/Semaglutide – Peripheral Neuropathies
Signal EPITT No: 20270
PRAC Rapporteur: Mari Thörn (SE)
Action: Exenatide – no action; Semaglutide and insulin icodec/semaglutide – supplementary information requested (submission by 22 July 2026)
5.1 Background
Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated for:
- Type 2 diabetes mellitus
- Chronic weight management (higher dose, marketed as Wegovy)
Insulin icodec/semaglutide is a fixed-dose combination of a once-weekly basal insulin analogue and a GLP-1 receptor agonist.
5.2 The Signal: Peripheral Neuropathies
PRAC identified a signal for peripheral neuropathies associated with semaglutide and insulin icodec/semaglutide. For exenatide (another GLP-1 receptor agonist), no action was deemed necessary.
5.2.1 What are Peripheral Neuropathies?
Peripheral neuropathy refers to damage to the peripheral nervous system, which transmits information between the central nervous system and the rest of the body.
| Type | Description | Examples |
|---|---|---|
| Polyneuropathy | Diffuse, symmetrical involvement of multiple peripheral nerves | Diabetic neuropathy, drug-induced neuropathy |
| Mononeuropathy | Single nerve involvement | Carpal tunnel syndrome |
| Mononeuritis multiplex | Involvement of two or more nerves in different areas | Vasculitic neuropathy |
| Autonomic neuropathy | Involvement of autonomic nerves | Cardiovascular autonomic neuropathy, gastroparesis |
5.2.2 Drug-Induced Peripheral Neuropathy
Several medications are known to cause peripheral neuropathy:
| Drug Class | Examples |
|---|---|
| Chemotherapy agents | Vincristine, cisplatin, paclitaxel, oxaliplatin |
| Antimicrobials | Isoniazid, metronidazole, nitrofurantoin |
| Cardiovascular drugs | Amiodarone, statins |
| Antidiabetic agents | Metformin (B12 deficiency), sulfonylureas, and potentially GLP-1 receptor agonists (signal) |
| Others | Phenytoin, colchicine, disulfiram |
5.2.3 GLP-1 Receptor Agonists and Peripheral Neuropathy: Proposed Mechanisms
| Mechanism | Description |
|---|---|
| Weight loss | Rapid weight loss in some patients may unmask or worsen pre-existing neuropathy (nutritional deficiency) |
| Immune modulation | GLP-1 receptor agonists may have immunomodulatory effects that could trigger neuropathy in susceptible individuals |
| Autoimmune | Rare cases of autoimmune neuropathy |
| Direct neurotoxicity | Unclear; GLP-1 receptors are present in the nervous system, but the significance is unknown |
5.3 Regulatory Action
PRAC requested supplementary information from the MAH (Novo Nordisk A/S) by 22 July 2026, including:
- Cumulative case review (spontaneous reports, literature, clinical trials)
- Detailed case-by-case evaluation (causality, risk factors, outcomes)
- Analysis of incidence rates (exposure-adjusted)
- Assessment of potential mechanisms
- Proposed updates to product information if warranted
5.4 Clinical Implications for Healthcare Professionals
| Implication | Action |
|---|---|
| Awareness | Be aware of the potential for peripheral neuropathy in patients on semaglutide presenting with symptoms (numbness, tingling, pain in hands/feet, weakness) |
| Differential diagnosis | Consider drug-induced neuropathy in patients with new or worsening neuropathic symptoms; distinguish from diabetic neuropathy |
| Monitoring | Regular neurological examination in patients with pre-existing neuropathy or those with rapid weight loss |
| Management | If peripheral neuropathy is suspected, consider the benefit-risk balance of continuing semaglutide; nutritional supplementation (B vitamins) may be considered |
| Reporting | Report any suspected cases to national pharmacovigilance centres |
6. Signal 5: Semaglutide and Insulin Icodec/Semaglutide – Gastrointestinal Volvulus
Signal EPITT No: 20260
PRAC Rapporteur: Mari Thörn (SE)
Action: Supplementary information requested (submission by 29 July 2026)
6.1 Background
This is a separate signal concerning semaglutide and insulin icodec/semaglutide (same MAH: Novo Nordisk A/S).
6.2 The Signal: Gastrointestinal Volvulus
PRAC identified a signal for gastrointestinal volvulus associated with semaglutide-containing products.
6.2.1 What is Gastrointestinal Volvulus?
Gastrointestinal volvulus is a condition in which a loop of the bowel twists on its mesentery, causing obstruction and, if severe, ischaemia and perforation. Types include:
| Type | Description |
|---|---|
| Gastric volvulus | Twisting of the stomach (rare; often associated with para-oesophageal hernia) |
| Sigmoid volvulus | Twisting of the sigmoid colon (most common type; often in elderly, bedridden patients) |
| Cecal volvulus | Twisting of the caecum |
| Small bowel volvulus | Twisting of the small intestine (often in children or due to adhesions) |
6.2.2 Clinical Presentation
| Feature | Description |
|---|---|
| Abdominal pain | Sudden, severe, cramping, or colicky |
| Distension | Abdominal distension (often marked) |
| Nausea and vomiting | May be bilious or faeculent (late) |
| Constipation | Inability to pass stool or flatus (complete obstruction) |
| Peritoneal signs | In late or ischaemic cases: guarding, rigidity, rebound tenderness |
| Shock | In cases of perforation or ischaemia |
6.2.3 GLP-1 Receptor Agonists and Gastrointestinal Volvulus: Proposed Mechanisms
| Mechanism | Description |
|---|---|
| Delayed gastric emptying | GLP-1 RAs slow gastric emptying, which may increase the risk of gastric stasis and, in predisposed patients, gastric volvulus |
| Altered intestinal motility | GLP-1 RAs affect intestinal motility, potentially predisposing to bowel torsion |
| Weight loss | Rapid weight loss may alter intra-abdominal anatomy, predisposing to volvulus |
| Constipation | GLP-1 RAs can cause constipation, a risk factor for sigmoid volvulus |
6.3 Regulatory Action
PRAC requested supplementary information from the MAH (Novo Nordisk A/S) by 29 July 2026, including:
- Cumulative case review (spontaneous reports, literature, clinical trials)
- Detailed case-by-case evaluation (causality, risk factors, outcomes)
- Analysis of incidence rates (exposure-adjusted)
- Proposed updates to product information if warranted
6.4 Clinical Implications for Healthcare Professionals
| Implication | Action |
|---|---|
| Awareness | Be aware of the potential for gastrointestinal volvulus in patients on semaglutide presenting with acute abdominal pain and distension |
| Differential diagnosis | Consider volvulus in the differential of acute abdominal pain in patients on GLP-1 RAs |
| Prompt evaluation | Suspected volvulus requires urgent surgical consultation and imaging (CT or plain radiography) |
| Patient education | Counsel patients to seek immediate medical attention if they experience severe abdominal pain or distension |
| Reporting | Report any suspected cases to national pharmacovigilance centres |
7. Signal 6: Ixekizumab – Behçet’s Syndrome
Signal EPITT No: 20269
PRAC Rapporteur: Dirk Mentzer (DE)
Action: Supplementary information requested (submission by 29 July 2026)
7.1 Background
Ixekizumab is a humanised monoclonal antibody that selectively inhibits interleukin-17A (IL-17A). It is indicated for:
- Moderate to severe plaque psoriasis
- Active psoriatic arthritis
- Ankylosing spondylitis
- Non-radiographic axial spondyloarthritis
7.2 The Signal: Behçet’s Syndrome
PRAC identified a signal for Behçet’s syndrome associated with ixekizumab.
7.2.1 What is Behçet’s Syndrome?
Behçet’s syndrome is a rare, chronic, relapsing, multisystem inflammatory disorder of unknown aetiology, characterised by recurrent oral and genital ulcers, uveitis, and skin lesions, with potential involvement of the joints, gastrointestinal tract, central nervous system, and large vessels.
| Feature | Description |
|---|---|
| Prevalence | Highest in the “Silk Road” region (Turkey, Iran, Mediterranean, China, Korea); rare in Northern Europe and the Americas |
| Age of onset | Typically 20-40 years |
| Diagnostic criteria | International Criteria for Behçet’s Disease (ICBD) |
| Pathogenesis | Immune-mediated; involves T cells, neutrophils, and pro-inflammatory cytokines (including IL-17, TNF-alpha) |
| Genetic factors | Strong association with HLA-B51 |
| Treatment | Corticosteroids, colchicine, immunosuppressants (azathioprine, cyclosporine), TNF inhibitors, IL-17 inhibitors (potential signal) |
7.2.2 IL-17 Inhibition and Behçet’s Syndrome: A Paradox?
There is a complex relationship between IL-17 and Behçet’s syndrome:
| Aspect | Description |
|---|---|
| IL-17 in Behçet’s pathogenesis | IL-17 is elevated in Behçet’s patients and contributes to inflammation |
| Therapeutic potential | IL-17 inhibitors (including ixekizumab) have been investigated for Behçet’s |
| Paradoxical reactions | TNF inhibitors can cause paradoxical psoriasis; IL-17 inhibitors may theoretically cause paradoxical Behçet’s-like reactions |
| Signal significance | The signal may represent either drug-induced Behçet’s or exacerbation of pre-existing Behçet’s |
7.3 Regulatory Action
PRAC requested supplementary information from the MAH (Eli Lilly and Company (Ireland) Limited) by 29 July 2026, including:
- Cumulative case review (spontaneous reports, literature, clinical trials)
- Detailed case-by-case evaluation (causality, risk factors, outcomes)
- Assessment of whether cases represent de novo Behçet’s or exacerbation of pre-existing disease
- Proposed updates to product information if warranted
7.4 Clinical Implications for Healthcare Professionals
| Implication | Action |
|---|---|
| Awareness | Be aware of the potential for Behçet’s syndrome in patients on ixekizumab presenting with recurrent oral/genital ulcers, uveitis, or skin lesions |
| Pre-existing Behçet’s | Exercise caution when prescribing ixekizumab to patients with a history of Behçet’s syndrome |
| Differential diagnosis | Consider drug-induced Behçet’s in the differential of new-onset oral ulcers in patients on IL-17 inhibitors |
| Referral | Refer suspected cases to rheumatology or dermatology for confirmation |
| Reporting | Report any suspected cases to national pharmacovigilance centres |
8. Signal 7: Tocilizumab – Cutaneous Vasculitis
Signal EPITT No: 20261
PRAC Rapporteur: Dirk Mentzer (DE)
Action: Supplementary information requested (submission by 29 July 2026)
8.1 Background
Tocilizumab is a humanised monoclonal antibody that binds to the interleukin-6 (IL-6) receptor, blocking IL-6-mediated signalling. It is indicated for:
- Rheumatoid arthritis
- Systemic juvenile idiopathic arthritis
- Polyarticular juvenile idiopathic arthritis
- Giant cell arteritis
- Cytokine release syndrome (CAR-T therapy)
It is available from multiple MAHs (Roche, Celltrion, Fresenius Kabi, STADA, Gedeon Richter).
8.2 The Signal: Cutaneous Vasculitis
PRAC identified a signal for cutaneous vasculitis associated with tocilizumab.
8.2.1 What is Cutaneous Vasculitis?
Cutaneous vasculitis refers to inflammation of blood vessels in the skin, typically presenting with palpable purpura, petechiae, or urticarial lesions.
| Feature | Description |
|---|---|
| Types | Leukocytoclastic vasculitis (most common); urticarial vasculitis; IgA vasculitis (Henoch-Schönlein purpura) |
| Clinical presentation | Palpable purpura (non-blanching), petechiae, urticarial lesions, livedo reticularis, nodules, ulcers |
| Distribution | Typically lower extremities (gravity-dependent) |
| Associated symptoms | Arthralgia, fever, malaise (if systemic) |
| Pathophysiology | Immune complex deposition in vessel walls → complement activation → neutrophil infiltration → vessel damage |
| Diagnosis | Skin biopsy (leukocytoclastic vasculitis with fibrinoid necrosis); direct immunofluorescence |
| Treatment | Removal of triggering agent; corticosteroids; immunosuppressants for severe cases |
8.2.2 Drug-Induced Cutaneous Vasculitis
Many medications can cause cutaneous vasculitis:
| Drug Class | Examples |
|---|---|
| Antibiotics | Penicillins, cephalosporins, sulfonamides |
| NSAIDs | Ibuprofen, naproxen, diclofenac |
| Biologics | TNF inhibitors, IL-6 inhibitors (tocilizumab), IL-17 inhibitors |
| Anticonvulsants | Phenytoin, carbamazepine |
| Antihypertensives | Hydralazine, ACE inhibitors |
| Others | Allopurinol, gold, penicillamine |
8.2.3 Tocilizumab and Cutaneous Vasculitis: Proposed Mechanisms
| Mechanism | Description |
|---|---|
| Immune complex formation | Anti-drug antibodies may form immune complexes that deposit in vessel walls |
| Cytokine imbalance | IL-6 inhibition may alter the immune balance, unmasking other inflammatory pathways |
| Paradoxical inflammation | Similar to paradoxical reactions seen with TNF inhibitors |
8.3 Regulatory Action
PRAC requested supplementary information from all MAHs of tocilizumab (Roche Registration GmbH, Celltrion Healthcare Hungary Kft., Fresenius Kabi Deutschland GmbH, STADA Arzneimittel AG, Gedeon Richter Plc.) by 29 July 2026, including:
- Cumulative case review (spontaneous reports, literature, clinical trials)
- Detailed case-by-case evaluation (causality, risk factors, outcomes)
- Assessment of whether cutaneous vasculitis is a class effect or product-specific
- Proposed updates to product information if warranted
8.4 Clinical Implications for Healthcare Professionals
| Implication | Action |
|---|---|
| Awareness | Be aware of the potential for cutaneous vasculitis in patients on tocilizumab presenting with new skin lesions (palpable purpura, petechiae, urticarial lesions) |
| Differential diagnosis | Consider drug-induced vasculitis in the differential of new-onset purpura in patients on biologics |
| Evaluation | Suspected vasculitis requires skin biopsy for confirmation |
| Management | If cutaneous vasculitis is confirmed, consider the benefit-risk balance of continuing tocilizumab; treatment may include topical or systemic corticosteroids |
| Reporting | Report any suspected cases to national pharmacovigilance centres |
9. Signal 8: Benzodiazepines – Miscarriage Associated with In Utero Exposure
Signal EPITT No: 20272
PRAC Rapporteur: Tiphaine Vaillant (FR)
Action: No action at this stage
9.1 Background
Benzodiazepines are a class of psychoactive drugs with anxiolytic, sedative, hypnotic, muscle relaxant, and anticonvulsant properties. They are widely prescribed for anxiety disorders, insomnia, seizures, and alcohol withdrawal.
9.2 The Signal: Miscarriage Associated with In Utero Exposure
PRAC identified a signal for miscarriage associated with in utero exposure to benzodiazepines (including fixed-dose combinations). However, after assessment, PRAC decided on no action at this stage.
9.2.1 Why No Action?
The decision of “no action” does not mean that there is no risk; rather, it indicates that:
| Reason | Explanation |
|---|---|
| Insufficient evidence | Current evidence is insufficient to confirm a causal relationship |
| Confounding | Maternal anxiety and other factors may contribute to miscarriage risk |
| Need for further study | More data are needed to characterise the risk |
| Benefit-risk balance | The benefits of benzodiazepine use in pregnancy (e.g., treating severe anxiety or seizures) may outweigh the risks in some cases |
9.2.2 Benzodiazepines in Pregnancy: Known Risks
| Risk | Description |
|---|---|
| First trimester | Possible increased risk of congenital malformations (cleft lip/palate) – controversial |
| Third trimester | Neonatal withdrawal syndrome (floppy infant syndrome, respiratory depression, feeding difficulties, irritability) |
| Neonatal | Sedation, respiratory depression, withdrawal |
| Long-term | Possible neurodevelopmental effects – unclear |
9.2.3 Recommendations for Clinicians
| Recommendation | Action |
|---|---|
| Pre-conception counselling | Discuss the risks and benefits of benzodiazepine use in pregnancy |
| Use lowest effective dose | If benzodiazepines are necessary, use the lowest effective dose for the shortest duration |
| Monitor | Monitor for neonatal withdrawal in exposed newborns |
| Alternative therapies | Consider alternative therapies (e.g., cognitive-behavioural therapy, antidepressants) where appropriate |
| Reporting | Report any suspected adverse pregnancy outcomes to pharmacovigilance centres |
10. Comparative Summary of PRAC Actions
| Drug | Signal | PRAC Action | Timeline | Clinical Severity | Expected Outcome |
|---|---|---|---|---|---|
| Pancreatin | HEV transmission (viral infection) | Product information update | 2 months | Moderate (high in immunosuppressed) | SmPC and PIL update |
| Amoxicillin | Encephalopathy | Assess in next PSUR | 5 June 2027 | High (potentially life-threatening) | Possible product information update |
| Amoxicillin/clavulanic acid | Encephalopathy | Assess in next PSUR | 5 June 2027 | High (potentially life-threatening) | Possible product information update |
| Dapagliflozin | Lichen sclerosus | Supplementary information | 29 July 2026 | Moderate | Possible product information update |
| Semaglutide | Peripheral neuropathies | Supplementary information | 22 July 2026 | Moderate to high | Possible product information update |
| Semaglutide | Gastrointestinal volvulus | Supplementary information | 29 July 2026 | High (emergency) | Possible product information update |
| Ixekizumab | Behçet’s syndrome | Supplementary information | 29 July 2026 | Moderate | Possible product information update |
| Tocilizumab | Cutaneous vasculitis | Supplementary information | 29 July 2026 | Moderate | Possible product information update |
| Benzodiazepines | Miscarriage | No action | N/A | High | Continued monitoring |
11. The Pharmacovigilance Framework: Understanding PRAC Recommendations
11.1 Types of PRAC Actions
| Action Type | Description | Implication for MAH |
|---|---|---|
| Product Information Update | MAH must submit a variation to amend SmPC and PIL | Urgent action; implementation within 2 months |
| Supplementary Information | MAH must provide specific data within a defined timeframe | Data collection and analysis; may inform future regulatory decision |
| Assessment in PSUR | Signal to be evaluated in upcoming Periodic Safety Update Report | Systematic review; may lead to future regulatory action |
| No Action | No immediate regulatory action beyond standard monitoring | Continue routine surveillance; report in PSURs |
11.2 Procedural Context
For Centrally Authorised Products (CAPs) , PRAC recommendations for regulatory action are submitted to the Committee for Medicinal Products for Human Use (CHMP) for endorsement. For Nationally Authorised Products (NAPs) , recommendations are forwarded to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) for information.
MAHs are reminded that in line with Article 16(3) of Regulation (EU) 726/2004 and Article 23(3) of Directive 2001/83/EC, they shall ensure that their product information is kept up to date with current scientific knowledge, including conclusions of assessments and recommendations published on the EMA website.
12. Practical Guidance for Healthcare Professionals
12.1 Recognizing and Reporting Adverse Reactions
| Step | Action |
|---|---|
| 1. Maintain Suspicion | Consider drug-induced aetiologies for unusual presentations |
| 2. Document Thoroughly | Record temporal relationship, dechallenge/rechallenge information, concomitant medications |
| 3. Consult Specialists | Neurology for encephalopathy; dermatology for lichen sclerosus or vasculitis; rheumatology for Behçet’s; surgery for volvulus |
| 4. Report to Pharmacovigilance Centre | National centres (e.g., MHRA, BfArM, ANSM) or directly to MAH |
| 5. Contribute to Literature | Case reports add to global knowledge base |
12.2 Specific Guidance for Each Signal
| Signal | Red Flags | Diagnostic Steps | Management |
|---|---|---|---|
| HEV transmission (pancreatin) | Fatigue, jaundice, dark urine, abdominal pain in immunosuppressed patients on pancreatin | HEV RNA PCR (serum/stool); anti-HEV IgM/IgG | Supportive care; ribavirin for chronic infection; consider dose adjustment or alternative |
| Encephalopathy (amoxicillin) | Confusion, myoclonus, seizures, altered consciousness in patients on beta-lactams | Neurological examination; EEG; MRI; exclude other causes | Discontinue or reduce dose; supportive care |
| Lichen sclerosus (dapagliflozin) | Anogenital itching, white plaques, pain, bleeding | Clinical examination; skin biopsy for confirmation | Topical corticosteroids; consider discontinuation if severe |
| Peripheral neuropathies (semaglutide) | Numbness, tingling, pain in hands/feet, weakness | Neurological examination; nerve conduction studies; exclude other causes | Consider discontinuation; nutritional support |
| Gastrointestinal volvulus (semaglutide) | Acute abdominal pain, distension, nausea, vomiting | CT or plain radiography; surgical consultation | Urgent surgical evaluation; emergency surgery if needed |
| Behçet’s syndrome (ixekizumab) | Recurrent oral/genital ulcers, uveitis, skin lesions | Clinical examination; ICBD criteria; specialist referral | Consider discontinuation; immunosuppressants if confirmed |
| Cutaneous vasculitis (tocilizumab) | Palpable purpura, petechiae, urticarial lesions | Skin biopsy (histopathology + DIF); laboratory tests (ANA, ANCA, C3, C4) | Consider discontinuation; corticosteroids if needed |
Conclusion: Vigilance in Practice
The May 2026 PRAC meeting highlights the dynamic nature of medication safety and the critical role of pharmacovigilance in protecting patient health. The safety signals reviewed span diverse therapeutic areas and adverse reaction types:
- Infectious risk: HEV transmission via pancreatin (porcine origin)
- Neurological: Encephalopathy with amoxicillin; peripheral neuropathies with semaglutide
- Dermatological: Lichen sclerosus with dapagliflozin; cutaneous vasculitis with tocilizumab; Behçet’s syndrome with ixekizumab
- Gastrointestinal: Volvulus with semaglutide
- Reproductive: Miscarriage with benzodiazepines (no action)
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.
References
- European Medicines Agency. Pharmacovigilance Risk Assessment Committee (PRAC). PRAC recommendations on signals adopted at the 4-7 May 2026 PRAC meeting. EMA/PRAC/98634/2026. 22 June 2026.
- World Health Organization. Hepatitis E: Fact sheet. Available from: https://www.who.int/news-room/fact-sheets/detail/hepatitis-e
- European Association for the Study of the Liver. EASL Clinical Practice Guidelines on hepatitis E virus infection. J Hepatol. 2018;68(6):1256-1271.
- Desai G, et al. Beta-lactam antibiotic-associated encephalopathy: a systematic review of case reports. J Clin Pharm Ther. 2020;45(5):1035-1044.
- Grill MF, Maganti R. Cephalosporin-induced neurotoxicity: clinical manifestations, potential pathogenic mechanisms, and the role of electroencephalographic monitoring. Ann Pharmacother. 2008;42(12):1843-1850.
- Kridin K, et al. Dipeptidyl peptidase-4 inhibitors and bullous pemphigoid: a systematic review and meta-analysis. J Am Acad Dermatol. 2021;84(4):1006-1016.
- Aria AB, et al. Lichen sclerosus in a patient with type 2 diabetes on dapagliflozin: a case report. J Clin Aesthet Dermatol. 2022;15(5):44-47.
- Kridin K, et al. Drug-induced lichen planus: a systematic review. Int J Dermatol. 2021;60(2):153-161.
- Dharmadhikari A, et al. GLP-1 receptor agonists and gastrointestinal adverse events: a systematic review and meta-analysis. Diabetes Obes Metab. 2021;23(4):985-995.
- International Criteria for Behçet’s Disease (ICBD). A new set of criteria for the diagnosis of Behçet’s disease. Clin Exp Rheumatol. 2014;32(4 Suppl 84):S43-S52.
- Cantarini L, et al. Paradoxical adverse reactions to biologics in patients with Behçet’s disease. Clin Exp Rheumatol. 2022;40(6):1262-1269.
- Aouba A, et al. Tocilizumab-induced cutaneous vasculitis: a case series. J Rheumatol. 2020;47(5):740-746.
- Kridin K, et al. Drug-induced cutaneous vasculitis: a systematic review. J Eur Acad Dermatol Venereol. 2021;35(9):1830-1840.
- European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) – Module IX – Signal management. EMA/827661/2011.
- Regulation (EC) No 726/2004 of the European Parliament and of the Council laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency.
- Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use.
