The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency met on 9–12 March 2026 to evaluate emerging safety signals for several medicinal products. This article provides a comprehensive medical analysis of the key safety signals reviewed, including a new aspect of a known risk (aseptic meningitis in healthy young adults following live attenuated chikungunya vaccination), a new adverse reaction for an established acetylcholinesterase inhibitor (nightmares with galantamine), and a request for supplementary information on the increased risk of ectopic pregnancy with lower-dose levonorgestrel intrauterine devices (13.5 mg).
Additionally, PRAC requested comments on proposed product information updates for gemcitabine regarding drug reaction with eosinophilia and systemic symptoms (DRESS). 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 9–12 March 2026, PRAC evaluated multiple safety signals and adopted recommendations ranging from product information updates to requests for supplementary information.
This article provides a detailed medical analysis of these signals, drawing on published literature to contextualize the regulatory findings and offer practical guidance for healthcare professionals.
2. Signal 1: Chikungunya Vaccine (Live) – New Aspect of Aseptic Meningitis Risk
2.1 Background: Chikungunya Virus and the Ixchiq Vaccine
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus transmitted primarily by Aedes aegypti and Aedes albopictus mosquitoes. The disease is characterized by acute febrile illness with severe, often debilitating polyarthralgia. Prior to 2024, no specific treatment or vaccine was available for chikungunya.
Ixchiq is a live attenuated chikungunya vaccine developed by Valneva Austria GmbH. It was authorized throughout the European Union in 2024. The vaccine is indicated for individuals aged 18 years and older and is not recommended for people who are immunodeficient or immunosuppressed.
2.2 The Signal: Aseptic Meningitis in Healthy Young Adults
PRAC initiated a safety signal review after a reported case of aseptic meningitis in a healthy young adult following vaccination with Ixchiq. While aseptic meningitis was already a known risk of the Ixchiq vaccine, most previously reported cases had occurred in people older than 65 years and those with multiple long-term medical conditions.
This case demonstrated that serious adverse reactions, including aseptic meningitis, can also occur in healthy young adults with no relevant comorbidities.
2.3 What is Aseptic Meningitis?
Aseptic meningitis is an inflammation of the meninges (the protective membranes covering the brain and spinal cord) not caused by bacterial infection. It is typically viral in origin but can also result from medications, vaccines, or other non-infectious causes.
2.4 Regulatory Action
PRAC recommended that the Marketing Authorisation Holder (MAH) of Ixchiq submit a variation within one month to amend the product information.
Key updates to the Summary of Product Characteristics (SmPC) include:
Section 4.4 – Special warnings and precautions for use:
*”Serious adverse reactions have been reported with the use of IXCHIQ, particularly in individuals aged 65 years and older and in individuals with multiple underlying chronic and/or uncontrolled medical conditions, but also in young adults with no relevant comorbidities (see section 4.8).
Severe reactogenicity or chikungunya-like adverse reactions may lead to deterioration of general condition including malaise and decreased appetite, exacerbation of pre-existing diseases, confusional state, aseptic meningitis, encephalopathy, or encephalitis, leading to falls, hospitalisation and death. Vaccinees should be instructed to promptly seek medical attention if they experience, after vaccination, symptoms suggestive of severe reactogenicity or severe chikungunya-like adverse reactions.”*
Section 4.8 – Undesirable effects:
*”In the post-marketing setting, serious adverse reactions have been reported, particularly in males aged 65 years and older with underlying chronic medical conditions such as cardiovascular disease, diabetes mellitus or chronic kidney disease, but also in young adults with no relevant comorbidities.
These adverse reactions included neurological events such as fatal encephalitis, aseptic meningitis, deterioration of general condition, and exacerbation of chronic medical conditions (see section 4.4).”*
2.5 Additional Regulatory Context
PRAC is also carrying out an evaluation of Ixchiq in the context of a regular 6-monthly Periodic Safety Update Report (PSUR) assessment, which will assess whether the newly available safety information has an impact on the balance of benefits and risks of Ixchiq. This is due to report in June 2026.
Note on US Status: The FDA suspended Ixchiq’s approval in the United States in August 2025 due to similar serious safety concerns, and the manufacturer voluntarily withdrew Ixchiq from the US market in January 2026.
2.6 Clinical Implications for Healthcare Professionals
3. Signal 2: Galantamine – Nightmares
3.1 Background: Galantamine
Galantamine is an acetylcholinesterase inhibitor (AChEI) with nicotinic receptor modulating properties. It is indicated for the symptomatic treatment of mild to moderate dementia of the Alzheimer’s type. It is available as both innovator and generic products.
3.2 The Signal: Nightmares
PRAC identified a safety signal for nightmares associated with galantamine use, which is a non-centralised procedure product (EPITT No 20196).
3.3 Evidence from Published Literature
The association between galantamine and nightmares is supported by published case reports and clinical studies.
Case Report (Corbo et al., 2013): A 90-year-old male with Alzheimer’s disease was initiated on galantamine 4 mg twice daily for 10 days, followed by 8 mg twice daily. The patient reported recurrent nightmares and associated anxiety that developed after initiating galantamine and temporally increased with dose titration. After discontinuation of galantamine, the patient reported no further occurrences of nightmares or anxiety.
Key Conclusion: Galantamine-associated nightmares are an uncommon adverse event and may have been exacerbated by rapid titration. Although such adverse events are unlikely to cause harm, they have the potential to decrease a patient’s quality of life and may require alternative therapy.
Clinical Trial Data: A double-blind, placebo-controlled study examined whether galantamine is associated with nighttime sleep-related problems. Comparisons between galantamine and placebo arms were not significant; however, due to the low frequency of nightmares in each group, the clinical relevance of this difference is unknown.
3.4 Mechanism
The mechanism by which galantamine may induce nightmares is not fully understood. As an acetylcholinesterase inhibitor, galantamine increases acetylcholine levels in the central nervous system. Acetylcholine plays a crucial role in the regulation of sleep architecture, particularly in REM sleep, which is associated with dreaming. Cholinomimetic actions have the potential to influence sleep quality and dream recall, and other AChEIs (e.g., donepezil) have also been associated with sleep-related adverse events.
3.5 Regulatory Action
PRAC recommended that MAHs of galantamine submit a variation within two months to amend the product information.
SmPC Section 4.8 – Undesirable effects:
Under SOC Psychiatric disorders with frequency “Uncommon”: Nightmare
Package Leaflet Section 4 – Possible side effects:
Under frequency “Uncommon”: Nightmares
3.6 Clinical Implications for Healthcare Professionals
4. Signal 3: Levonorgestrel Intrauterine Device 13.5 mg – Increased Risk of Ectopic Pregnancy
4.1 Background
Levonorgestrel-releasing intrauterine devices (LNG-IUDs) are effective contraceptives that work primarily by thickening cervical mucus and thinning the endometrium. Different doses are available: 13.5 mg (e.g., Jaydess), 19.5 mg (e.g., Kyleena), and 52 mg (e.g., Mirena).
4.2 The Signal: Increased Risk of Ectopic Pregnancy
PRAC requested supplementary information (submission by 6 May 2026) for the signal concerning an increased risk of ectopic pregnancy with the levonorgestrel 13.5 mg intrauterine device (EPITT No 20251).
4.3 Evidence from Published Studies
Roland et al. (2025) – NEJM Evidence:
A nationwide cohort study using data from the French National Healthcare Data System (SNDS) examined ectopic pregnancy risk with varying hormonal IUD dosages compared with copper IUDs.
Study Population:
| IUD Type | Number of Women |
|---|---|
| Levonorgestrel 13.5 mg | 45,450 |
| Levonorgestrel 19.5 mg | 212,301 |
| Levonorgestrel 52 mg | 244,871 |
| Copper IUD | 1,033,505 |
Results – Incidence Rates per 100 Person-Years:
| IUD Type | Incidence Rate (95% CI) |
|---|---|
| Levonorgestrel 13.5 mg | 0.18 (0.14–0.23) |
| Levonorgestrel 19.5 mg | 0.10 (0.08–0.11) |
| Levonorgestrel 52 mg | 0.04 (0.03–0.05) |
| Copper IUD | 0.07 (0.07–0.08) |
Hazard Ratios Compared with Copper IUD:
| IUD Type | Hazard Ratio (95% CI) |
|---|---|
| Levonorgestrel 13.5 mg | 2.57 (1.92–3.43) |
| Levonorgestrel 19.5 mg | 1.37 (1.15–1.62) |
| Levonorgestrel 52 mg | 0.62 (0.49–0.80) |
Conclusion: The highest dose (levonorgestrel 52 mg) was associated with the lowest risk of ectopic pregnancy within 1 year compared with copper IUDs, whereas the 13.5 mg hormonal IUD was associated with the highest risk.
4.4 Why This Matters
If a woman becomes pregnant with an IUD in place, the likelihood of ectopic pregnancy is increased. For the 13.5 mg LNG-IUD, the risk of ectopic pregnancy is more than 2.5 times higher than with copper IUDs, and substantially higher than with higher-dose LNG-IUDs.
4.5 Clinical Implications for Healthcare Professionals
| Implication | Action |
|---|---|
| Informed consent | Counsel women considering the 13.5 mg LNG-IUD about the increased relative risk of ectopic pregnancy compared with other IUD options |
| Pregnancy testing | In women using LNG-IUDs who present with signs or symptoms of pregnancy, consider ectopic pregnancy in the differential diagnosis |
| Early recognition | Ectopic pregnancy symptoms include abdominal pain, vaginal bleeding, and amenorrhoea; rupture can be life-threatening |
| Device removal | If a woman becomes pregnant with an IUD in place, remove the device if the string is visible; monitor closely |
| Reporting | Report suspected cases to national pharmacovigilance centres |
5. Signal 4: Gemcitabine – Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
5.1 Background: Gemcitabine
Gemcitabine is an antimetabolite chemotherapeutic agent used in the treatment of various malignancies, including breast cancer, ovarian cancer, non-small cell lung cancer, pancreatic cancer, and bladder cancer.
5.2 The Signal: DRESS Syndrome
PRAC requested that MAHs (Cheplapharm Arzneimittel GmbH, Sun Pharmaceutical Industries Europe B.V.) provide comments to the proposed updates to the product information for gemcitabine regarding drug reaction with eosinophilia and systemic symptoms (DRESS) (EPITT No 20256), with submission by 8 May 2026.
5.3 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.
| Feature | Description |
|---|---|
| Definition | Severe cutaneous adverse reaction (SCAR) with multi-organ involvement |
| Onset | Typically 2–8 weeks after drug exposure |
| Clinical features | Fever, widespread skin rash, lymphadenopathy, eosinophilia, atypical lymphocytes, and internal organ involvement (hepatitis, nephritis, pneumonitis, myocarditis) |
| Mortality | 5–10% |
| Diagnosis | Clinical (RegiSCAR criteria) |
5.4 Gemcitabine and DRESS – Regulatory Context
The FDA has already recognized the risk of SCARs, including DRESS, with gemcitabine. Pfizer’s patient counseling information advises:
“Advise patients of the risks of SCARs, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). Instruct patients to immediately contact their healthcare provider should any signs or symptoms of severe skin rash or skin peeling, blistering and/or mouth sores occur.”
PRAC’s request for comments suggests that the committee is considering updating the EU product information to align with current knowledge of this risk.
5.5 Clinical Implications for Healthcare Professionals
| Implication | Action |
|---|---|
| Awareness | Be aware that DRESS syndrome is a potential adverse reaction to gemcitabine |
| Early recognition | DRESS typically presents 2–8 weeks after drug initiation with fever, rash, and systemic symptoms |
| Diagnosis | Suspect DRESS in patients on gemcitabine who develop skin rash with eosinophilia and/or systemic symptoms |
| Management | Discontinue gemcitabine immediately if DRESS is suspected; initiate supportive care and systemic corticosteroids as indicated |
| Reporting | Report any suspected cases to national pharmacovigilance centres |
6. Summary Table of PRAC March 2026 Recommendations
| Signal | Product | PRAC Action | Timeline | Clinical Severity |
|---|---|---|---|---|
| Aseptic meningitis (new aspect) | Chikungunya vaccine (Ixchiq) | Product information update | 1 month | High (neurological) |
| Nightmares | Galantamine | Product information update | 2 months | Low (quality of life) |
| Increased ectopic pregnancy risk | Levonorgestrel IUD 13.5 mg | Supplementary information | 6 May 2026 | High (potentially life-threatening) |
| DRESS syndrome | Gemcitabine | Comments to proposed PI updates | 8 May 2026 | High (potentially fatal) |
7. Practical Guidance for Healthcare Professionals
Recognising and Reporting Adverse Reactions
| Signal | Red Flags | Diagnostic Steps | Management |
|---|---|---|---|
| Aseptic meningitis (chikungunya vaccine) | Headache + neck stiffness + photophobia post-vaccination; confusion, sleepiness, seizures | Lumbar puncture; CSF PCR for vaccine-strain virus | Supportive care; report to pharmacovigilance centre |
| Nightmares (galantamine) | Distressing dreams, sleep disturbances, anxiety | Clinical history; temporal relationship with drug initiation or dose increase | Consider slower dose titration; if persistent, consider alternative therapy |
| Ectopic pregnancy (LNG-IUD) | Abdominal pain, vaginal bleeding, amenorrhoea; positive pregnancy test | β-hCG levels; transvaginal ultrasound | Remove IUD if strings visible; treat with methotrexate or surgery; report |
| DRESS (gemcitabine) | Fever + rash + eosinophilia + systemic symptoms (hepatitis, nephritis) 2-8 weeks after drug start | CBC with differential; LFTs, renal function; skin biopsy; rule out other causes | Discontinue drug; corticosteroids; supportive care; report |
8. Conclusion
The March 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:
- Chikungunya vaccine: Aseptic meningitis – previously known to occur in elderly and comorbid patients – has now been reported in a healthy young adult. Clinicians should counsel all vaccine recipients about this risk and advise prompt medical attention for neurological symptoms.
- Galantamine: Nightmares are an uncommon but quality-of-life-impacting adverse effect. Slow dose titration may reduce risk; alternative therapy may be needed for affected patients.
- Levonorgestrel IUD 13.5 mg: The lower-dose device carries a significantly higher risk of ectopic pregnancy compared with higher-dose LNG-IUDs and copper IUDs. Informed consent should include discussion of this risk.
- Gemcitabine: DRESS syndrome is a rare but severe hypersensitivity reaction. Early recognition and prompt drug discontinuation are essential.
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 9-12 March 2026 PRAC meeting. EMA/PRAC/44423/2026. 7 April 2026. [citation:PRAC_Mar2026]
- Meredith S. Meningitis Risk for Young Adults With Chikungunya Vaccine. Medscape. March 13, 2026. Available from: https://www.medscape.com/viewarticle/meningitis-risk-young-adults-chikungunya-vaccine-2026a10007ty
- Corbo JM, et al. Galantamine-associated nightmares and anxiety. Consult Pharm. 2013;28(4):243-6. doi:10.4140/TCP.n.2013.243
- Roland N, et al. Intrauterine Devices and Risk of Ectopic Pregnancy. NEJM Evid. 2025;4(12):EVIDoa2500117. doi:10.1056/EVIDoa2500117
- The ObG Project. Do Lower Dose Levonorgestrel IUDs Carry a Higher Risk of Ectopic Pregnancy? January 15, 2026. Available from: https://www.obgproject.com/2026/01/15/do-lower-dose-levonorgestrel-iuds-carry-a-higher-risk-of-ectopic-pregnancy/
- Pfizer Medical. Gemcitabine injection solution: Patient Counseling Information. Available from: https://www.pfizermedical.com/gemcitabine/info-for-patient
- Stahl SM, et al. Examination of nighttime sleep-related problems during double-blind, placebo-controlled trials of galantamine in patients with Alzheimer’s disease. Curr Med Res Opin. 2004;20(4):517-524.
