The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency met on 6–9 July 2026 and adopted important recommendations for multiple safety signals. This article provides a comprehensive medical analysis of the signals reviewed, including product information updates for desogestrel/etonogestrel and meningioma, levonorgestrel intrauterine systems and ectopic pregnancy, and recommendations for supplementary information concerning atogepant and insomnia, CGRP antagonists and Raynaud’s phenomenon, oseltamivir safety in critically ill patients, sacituzumab govitecan and interstitial lung disease, selpercatinib and intestinal lymphangiectasia, and sevoflurane and acute encephalopathy in patients carrying the mitochondrial DNA variant m.11232T>C. For each signal, we explore the clinical presentation, pathophysiology, epidemiological evidence, regulatory actions, and practical implications for healthcare professionals, drawing on published literature and regulatory documents.
1. Introduction: The Role of PRAC in Medication Safety
The Pharmacovigilance Risk Assessment Committee (PRAC) is the European Medicines Agency’s committee responsible for evaluating safety signals for human medicines. At its meeting of 6–9 July 2026, PRAC adopted important recommendations for multiple safety signals, ranging from product information updates to requests for supplementary information and Direct Healthcare Professional Communications (DHPCs).
2. Signal 1: Desogestrel and Etonogestrel – Risk of Meningioma
Signal EPITT No: 20167
PRAC Rapporteur: Karin Bolin (SE)
Action: Product information update; DHPC distribution
2.1 Background
Desogestrel and etonogestrel are progestogens used for contraception. Desogestrel-containing medicines are available as oral tablets, while etonogestrel-containing medicines are available as implants or, in combination with ethinylestradiol, as vaginal rings. Desogestrel is metabolised to etonogestrel, which is the active metabolite.
2.2 The Signal: Meningioma
PRAC identified a signal for meningioma associated with current, prolonged use (>1 year) of desogestrel- or etonogestrel-containing contraceptives.
2.2.1 What is Meningioma?
Meningiomas are tumours of the tissue layer (meninges) surrounding the brain and spinal cord. Key characteristics include:
2.2.2 Epidemiological Evidence
The PRAC recommendations were based on a large French case-control study conducted using the Système National des Données de Santé (SNDS). The study included 8,391 women who had undergone intracranial surgery for meningioma, compared to 83,910 controls.
Additional studies corroborate these findings. A Danish nested case-control study of 1,473 women with meningioma matched with 14,717 controls found:
- Desogestrel in combined oral contraceptives: OR 1.66 (95% CI: 1.31–2.10)
- Desogestrel as progestogen-only pill: OR 1.73 (95% CI: 1.17–2.56)
- Injectable medroxyprogesterone: OR 4.55 (95% CI: 2.19–9.45) – highest risk
Progestogens previously associated with meningioma that increase risk in combination with desogestrel/etonogestrel include cyproterone, nomegestrol, medroxyprogesterone, and chlormadinone.
2.3 Regulatory Action
PRAC recommended the following changes:
Contraindications (SmPC Section 4.3):
- Meningioma or history of meningioma
Warnings (SmPC Section 4.4):
- Current, prolonged use (≥1 year) associated with small increased risk
- Risk increases with longer duration
- Risk may be higher with previous progestogen exposure
- Monitor for signs and symptoms of meningioma
- If diagnosed with meningioma, treatment must be discontinued
Undesirable effects (SmPC Section 4.8):
- Meningioma added with frequency “not known”
DHPC: A Direct Healthcare Professional Communication was agreed to inform healthcare professionals of the small increased risk.
2.4 Clinical Implications
A 2025 study in the BMJ suggested that desogestrel should be discontinued if an intracranial meningioma is identified, with patients monitored clinically and radiologically rather than undergoing immediate surgery.
3. Signal 2: Levonorgestrel Intrauterine Device 13.5 mg (Jaydess) – Increased Risk of Ectopic Pregnancy
Signal EPITT No: 20251
PRAC Rapporteur: Dennis Lex (DE)
Action: Product information update
3.1 Background
Jaydess is a low-dose levonorgestrel-releasing intrauterine system (LNG-IUS) containing 13.5 mg of levonorgestrel. It is indicated for contraception and is not first choice for nulliparous women due to limited clinical experience.
3.2 The Signal: Ectopic Pregnancy
PRAC identified an increased risk of ectopic pregnancy with the levonorgestrel 13.5 mg IUS compared to other IUSs and copper IUDs, based on a nationwide cohort study using data from the French National Healthcare Data System.
3.2.1 What is Ectopic Pregnancy?
Ectopic pregnancy is a pregnancy that develops outside the uterine cavity, most commonly in the fallopian tube. It is a serious, potentially life-threatening condition requiring immediate medical attention.
Risk factors:
- Previous ectopic pregnancy
- Tubal surgery
- Pelvic infection
3.2.2 Epidemiological Evidence
A nationwide cohort study compared hormonal IUSs and copper IUDs. At 1 year, ectopic pregnancy incidence rates per 100 woman-years were:
| Device | Incidence Rate (95% CI) | Hazard Ratio vs Copper IUD (95% CI) |
|---|---|---|
| Levonorgestrel 13.5 mg IUS (Jaydess) | 0.18 | 2.57 (1.92–3.43) |
| Levonorgestrel 19.5 mg IUS | 0.10 | 1.37 (1.15–1.62) |
| Levonorgestrel 52 mg IUS | Not specified | 0.62 (0.49–0.80) |
| Copper IUDs | Reference | 1.00 (reference) |
In clinical trials, the overall incidence of ectopic pregnancy with Jaydess was approximately 0.11 per 100 woman-years, with approximately half of pregnancies that occur during Jaydess use being ectopic.
3.3 Regulatory Action
PRAC recommended updating the product information to reflect the higher incidence rates of ectopic pregnancy with Jaydess (13.5 mg) compared to other IUSs and copper IUDs. Key additions include:
- Women considering Jaydess should be counselled on signs, symptoms, and risks of ectopic pregnancy
- For women who become pregnant while using Jaydess, possibility of ectopic pregnancy must be considered and evaluated
- Because an ectopic pregnancy may compromise future fertility, benefits and risks should be carefully evaluated, particularly for nulliparous women
3.4 Clinical Implications
4. Signal 3: Atogepant – Insomnia
Signal EPITT No: 20291
PRAC Rapporteur: Rugile Pilviniene (LT)
Action: Assess in ongoing PSUR (submission by 30 September 2026)
4.1 Background
Atogepant is a calcitonin gene-related peptide (CGRP) receptor antagonist (gepant) indicated for the preventive treatment of migraine in adults. It is available as 10 mg and 60 mg tablets.
4.2 The Signal: Insomnia
PRAC identified a signal for insomnia associated with atogepant.
4.2.1 Clinical Context
CGRP and its receptors are involved in various physiological processes beyond migraine pathophysiology, including sleep regulation. Emerging data suggest that anti-CGRP monoclonal antibodies and gepants, particularly erenumab, galcanezumab, and atogepant, can improve subjective sleep quality in some cases, but sleep-related adverse events have also been reported.
4.2.2 Evidence
A pharmacovigilance analysis found:
- Insomnia was reported in less than 1% of cases for rimegepant, atogepant, and ubrogepant
- Abnormal dreams and nightmares were particularly noted with atogepant, with FAERS analyses showing a robust signal (ROR 7.74)
- Most commonly reported adverse drug reactions with atogepant are nausea (9%), constipation (8%), and fatigue/somnolence (5%)
4.3 Regulatory Action
PRAC requested the MAH (AbbVie Deutschland GmbH & Co. KG) to assess the insomnia signal in the ongoing Periodic Safety Update Report (PSUR) with submission by 30 September 2026.
4.4 Clinical Implications
| Implication | Action |
|---|---|
| Patient counselling | Inform patients about potential sleep-related adverse effects, including insomnia, abnormal dreams, and nightmares |
| Monitoring | Assess sleep quality during atogepant treatment |
| Reporting | Report any suspected cases of insomnia or sleep disturbances to national pharmacovigilance centres |
5. Signal 4: CGRP Antagonists – Raynaud’s Phenomenon
Signal EPITT No: 20292
PRAC Rapporteur: Terhi Lehtinen (FI)
Action: Supplementary information requested (submission by 14 October 2026)
5.1 Background
This signal covers multiple CGRP-targeting therapies:
- Gepants (small molecules): Atogepant, rimegepant
- CGRP monoclonal antibodies: Eptinezumab, erenumab, fremanezumab, galcanezumab
5.2 The Signal: Raynaud’s Phenomenon
PRAC identified a signal for Raynaud’s phenomenon associated with CGRP antagonists.
5.2.1 What is Raynaud’s Phenomenon?
Raynaud’s phenomenon is a vasospastic disorder causing episodes of reduced blood flow to the extremities, typically the fingers and toes.
Features:
- Fingers or toes become numb, cool, or painful
- Colour changes from pale to blue to red
- Symptoms typically occur after a median of 71 days following dosing with CGRP monoclonal antibodies
5.2.2 Pathophysiological Mechanism
CGRP is a potent vasodilator. By blocking CGRP or its receptor, CGRP antagonists may:
- Reduce compensatory vasodilation in response to cold or stress
- Exacerbate underlying vasospastic tendencies
- Unmask or worsen pre-existing Raynaud’s phenomenon
A 2026 disproportionality study investigating the potential risk and possible mechanisms of Raynaud’s phenomenon associated with CGRP antagonists found that erenumab had the highest number of reports, while fremanezumab resulted in the strongest AE signals.
5.2.3 Clinical Evidence
- In March 2025, FDA labelling for gepants was updated to include potential risks of hypertension and Raynaud’s phenomenon
- The CGRP mAb erenumab label also warns of new-onset or worsening hypertension
- Raynaud’s phenomenon has been reported in 5.3% of cases with microvascular complications (5 cases erenumab, 3 galcanezumab, 1 fremanezumab)
- Contraindicated if severe Raynaud’s with microvascular lesions and/or sclerodermia
5.3 Regulatory Action
PRAC requested supplementary information from all MAHs by 14 October 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
5.4 Clinical Implications
| Implication | Action |
|---|---|
| Pre-existing Raynaud’s | Monitor patients with a history of Raynaud’s phenomenon for worsening or recurrence |
| New-onset symptoms | Advise patients to report numbness, coolness, pain, or colour changes in fingers or toes |
| Monitoring | Discontinue therapy if signs or symptoms of Raynaud’s phenomenon develop |
| Contraindications | Exercise caution or consider alternative therapy in patients with severe Raynaud’s with microvascular lesions or sclerodermia |
| Reporting | Report any suspected cases to national pharmacovigilance centres |
6. Signal 5: Oseltamivir and Intravenous Zanamivir – New Information on Safety in Critically Ill Patients with Influenza
Signal EPITT No: 20299
PRAC Rapporteur: Terhi Lehtinen (FI)
Action: Supplementary information requested (submission by 26 August 2026)
6.1 Background
Oseltamivir (Tamiflu) is a neuraminidase inhibitor that is the current first-line antiviral treatment for influenza in critically ill patients. Zanamivir is another neuraminidase inhibitor available in intravenous formulation.
6.2 The Signal: Safety in Critically Ill Patients
PRAC identified a signal concerning the safety and efficacy of oseltamivir in critically ill patients with influenza, triggered by preliminary results from the REMAP-CAP trial.
6.2.1 The REMAP-CAP Trial
On 10 June 2026, the REMAP-CAP trial released preliminary results suggesting that oseltamivir:
- Is not effective in adult patients with influenza in critical care
- May be harmful
The analysis indicated:
- <2% chance oseltamivir was effective
- 98% chance it was harmful in this population
Subsequent guidelines, including the Australian Therapeutic Guidelines, have recommended against routinely using oseltamivir in critically ill patients aged 12 and older.
6.3 Clinical Significance
This signal is particularly significant because:
- Critically ill influenza patients represent a high-risk population
- Oseltamivir has been standard of care in ICU settings
- Potential harm must be balanced against the risk of untreated influenza
6.4 Regulatory Action
PRAC requested supplementary information from the MAHs (Roche Registration GmbH, GlaxoSmithKline Trading Services Limited) by 26 August 2026, including:
- Updated analysis of efficacy and safety data in critically ill patients
- Assessment of risk-benefit balance in this population
- Proposed updates to product information if warranted
6.5 Clinical Implications
| Implication | Action |
|---|---|
| Re-evaluate standard practice | Critically ill influenza patients may not benefit from oseltamivir; potential harm must be considered |
| Individualised decision-making | Consider patient-specific factors; alternative antivirals (baloxavir, peramivir) may be options |
| Monitor closely | For adverse effects in critically ill patients receiving oseltamivir |
| Reporting | Report any suspected adverse reactions in critically ill patients |
7. Signal 6: Sacituzumab Govitecan – Interstitial Lung Disease
Signal EPITT No: 20290
PRAC Rapporteur: Bianca Mulder (NL)
Action: Supplementary information requested (submission by 23 September 2026)
7.1 Background
Sacituzumab govitecan is a new-generation antibody-drug conjugate (ADC) indicated for metastatic triple-negative breast cancer and other solid tumours. It consists of a monoclonal antibody targeting Trop-2 linked to the active metabolite of irinotecan (SN-38).
7.2 The Signal: Interstitial Lung Disease
PRAC identified a signal for interstitial lung disease (ILD) associated with sacituzumab govitecan.
7.2.1 What is Drug-Induced Interstitial Lung Disease?
Drug-induced ILD is a spectrum of pulmonary disorders characterised by inflammation and fibrosis of the lung interstitium. In the context of ADCs, ILD is a known class effect.
Mechanism: Drug-induced ILD may occur through:
- Direct cytotoxicity to pneumocytes
- Immune-mediated inflammation
- Off-target effects of the payload or linker
7.2.2 Clinical Evidence
A 2026 case report described interstitial pneumonitis related to sacituzumab govitecan in a patient with metastatic triple-negative breast cancer. Key points:
- Sacituzumab-govitecan-related pulmonary toxicity is rare
- Early detection of drug-induced interstitial lung disease is critical
- Management requires drug discontinuation and immediate steroid therapy
- Interestingly, the patient was successfully rechallenged with a reduced dose without recurrent pneumonitis
7.3 Regulatory Action
PRAC requested supplementary information from the MAH (Gilead Sciences Ireland UC) by 23 September 2026.
7.4 Clinical Implications
| Implication | Action |
|---|---|
| Awareness | Maintain high index of suspicion for ILD in patients on sacituzumab govitecan presenting with respiratory symptoms |
| Monitoring | Regular pulmonary assessment; consider baseline and interval pulmonary function tests |
| Early detection | Prompt evaluation of new or worsening cough, dyspnoea, or hypoxia |
| Management | Discontinue sacituzumab govitecan if ILD suspected; initiate corticosteroids |
| Rechallenge | May be possible at reduced dose in selected patients |
| Reporting | Report any suspected cases to national pharmacovigilance centres |
8. Signal 7: Selpercatinib – Intestinal Lymphangiectasia
Signal EPITT No: 20289
PRAC Rapporteur: Bianca Mulder (NL)
Action: Assess in next PSUR (submission by 17 January 2027)
8.1 Background
Selpercatinib is a selective RET (rearranged during transfection) inhibitor indicated for RET fusion-positive lung cancers and other RET-altered solid tumours.
8.2 The Signal: Intestinal Lymphangiectasia
PRAC identified a signal for intestinal lymphangiectasia associated with selpercatinib.
8.2.1 What is Intestinal Lymphangiectasia?
Intestinal lymphangiectasia is a disorder characterised by:
- Dilated intestinal lacteals (lymphatic vessels in the intestinal villi)
- Potential lymph leakage into the intestinal lumen
- Resulting in protein-losing enteropathy, hypoalbuminaemia, lymphopenia, and oedema
A 2026 systematic analysis described this as “an underrecognised disorder”.
8.2.2 Clinical Evidence
A 2026 report titled “Brief Report: Intestinal Lymphangiectasia With Selpercatinib and Pralsetinib Treatment” identified drug-induced intestinal lymphangiectasia as an emerging complication.
Key findings:
- Drug-induced IL occurs with selpercatinib or pralsetinib treatment
- First systematic analysis of IL in RET inhibitor-treated patients
- Mechanism likely related to RET inhibition affecting lymphatic development and function
8.3 Regulatory Action
PRAC requested the MAH (Eli Lilly Nederland B.V.) to assess the signal in the next PSUR with submission by 17 January 2027.
8.4 Clinical Implications
| Implication | Action |
|---|---|
| Awareness | Consider intestinal lymphangiectasia in patients on selpercatinib presenting with oedema, hypoalbuminaemia, or lymphopenia |
| Diagnostic evaluation | Endoscopy with biopsy may show dilated lacteals; further investigations may include faecal alpha-1 antitrypsin clearance |
| Management | May require dietary modification (low-fat diet, medium-chain triglycerides), albumin supplementation, or treatment adjustment |
| Reporting | Report any suspected cases to national pharmacovigilance centres |
9. Signal 8: Sevoflurane – Acute Encephalopathy in Patients Carrying the Mitochondrial DNA Variant m.11232T>C
Signal EPITT No: 20285
PRAC Rapporteur: Eamon O Murchu (IE)
Action: Supplementary information requested (submission by 23 September 2026)
9.1 Background
Sevoflurane is a volatile halogenated anaesthetic agent widely used for induction and maintenance of general anaesthesia.
9.2 The Signal: Acute Encephalopathy
PRAC identified a signal for acute encephalopathy in patients carrying the mitochondrial DNA variant m.11232T>C following sevoflurane exposure.
9.2.1 The Mitochondrial DNA Variant
The m.11232T>C variant is located in the MT-ND4 gene, which encodes a subunit of mitochondrial respiratory chain complex I (NADH:ubiquinone oxidoreductase). This variant has been identified in patients of Venezuelan ancestry.
9.2.2 Pathophysiology
In vitro studies have shown that:
- Sevoflurane exposure in cells carrying the m.11232T>C genetic variant induces a pronounced suppression of mitochondrial oxygen consumption
- This leads to mitochondrial dysfunction and impaired cellular energy production
- Neural tissue is particularly vulnerable due to its high energy demands
9.2.3 Clinical Evidence
A 2026 case report described a 20-year-old woman who developed acute encephalopathy after uneventful general anaesthesia with sevoflurane. Genetic testing confirmed the mitochondrial variant m.11232T>C in the MT-ND4 gene, previously described only in paediatric patients.
A Spanish alert (GTSAD-SEMICYUC) identified susceptibility to the MT-ND4 mitochondrial variant with the use of halogenated gases for ICU sedation.
Key findings:
- Patients sharing a mitochondrial DNA haplotype that includes the m.11232T>C variant may be at increased risk of severe neurologic deterioration after sevoflurane exposure
- Adult and paediatric patients of Venezuelan ancestry may carry this mitochondrial gene mutation
- Anaesthesia professionals are encouraged to avoid sevoflurane and other volatile anaesthetic agents in susceptible patients
9.3 Regulatory Action
PRAC requested supplementary information from the MAHs (AbbVie SA, Baxter SA, Piramal Critical Care B.V.) by 23 September 2026.
9.4 Clinical Implications
| Implication | Action |
|---|---|
| Risk identification | Consider patient ancestry (Venezuelan origin) as a risk factor |
| Pre-anaesthetic assessment | Ask about family history of anaesthetic complications |
| Alternative agents | Consider avoiding sevoflurane and other volatile anaesthetics in at-risk patients; use midazolam or other agents |
| Monitoring | If volatile anaesthetics are used, monitor closely for signs of encephalopathy |
| Reporting | Report any suspected cases of acute encephalopathy following sevoflurane exposure |
10. Additional Actions: Venlafaxine Cardiotoxicity
Signal EPITT No: 20230
PRAC Rapporteur: Karin Bolin (SE)
Action: Monitor in PSUR
Venlafaxine is a serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant. PRAC recommended monitoring the signal of cardiotoxicity in PSURs. Healthcare professionals should maintain vigilance for cardiovascular adverse effects in patients on venlafaxine.
11. Summary of PRAC Actions
| Drug | Signal | PRAC Action | Clinical Severity | Expected Outcome |
|---|---|---|---|---|
| Desogestrel/Etonogestrel | Meningioma | Product information update; DHPC | Moderate (rare but serious) | SmPC/PIL update; contraindication; DHPC |
| Levonorgestrel 13.5 mg IUS | Ectopic pregnancy | Product information update | High (potentially life-threatening) | SmPC/PIL update |
| Atogepant | Insomnia | Assess in PSUR | Mild-moderate | Possible future product information update |
| CGRP antagonists | Raynaud’s phenomenon | Supplementary information | Moderate | Possible product information update |
| Oseltamivir | Safety in critical illness | Supplementary information | High | Possible practice-changing |
| Sacituzumab govitecan | Interstitial lung disease | Supplementary information | High | Possible product information update |
| Selpercatinib | Intestinal lymphangiectasia | Assess in PSUR | Moderate | Possible product information update |
| Sevoflurane | Acute encephalopathy (mitochondrial variant) | Supplementary information | High (life-threatening) | Possible product information update |
12. Practical Guidance for Healthcare Professionals
12.1 Recognizing and Reporting Adverse Reactions
12.2 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
13. Conclusion
The July 2026 PRAC recommendations highlight the dynamic nature of pharmacovigilance and the ongoing need for post-marketing safety surveillance. The eight signals discussed in this article demonstrate the diverse ways in which adverse reactions can manifest:
- Hormonal contraceptives – Meningioma risk with desogestrel/etonogestrel (NNH 67,300) and increased ectopic pregnancy risk with low-dose LNG-IUS
- Migraine therapies – Insomnia with atogepant and Raynaud’s phenomenon with CGRP antagonists
- Infectious disease treatments – Potential harm with oseltamivir in critically ill influenza patients
- Oncological therapies – Interstitial lung disease with sacituzumab govitecan and intestinal lymphangiectasia with selpercatinib
- Anaesthetic agents – Acute encephalopathy with sevoflurane in patients with mitochondrial DNA variant m.11232T>C
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 6-9 July 2026 PRAC meeting. EMA/PRAC/155652/2026. 3 August 2026.
- European Medicines Agency. Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 6-9 July 2026. 10 July 2026.
- Roland N, Kolla E, Baricault B, et al. Oral contraceptives with progestogens desogestrel or levonorgestrel and risk of intracranial meningioma: national case-control study. BMJ. 2025;389:e083981.
- Hasselblad Lundstrøm N, et al. Contraceptive Progestogens and Incident Meningioma. JAMA Netw Open. 2026;9(7):e2622603.
- Sanz-Pons J, et al. Effects of a Mitochondrial Genetic Variant on Sevoflurane Hypersensitivity. Anesthesiology. 2026;144(6).
- Brief Report: Intestinal Lymphangiectasia With Selpercatinib and Pralsetinib Treatment. J Thorac Oncol. 2026 Mar 31:103704.
- Interstitial pneumonitis related to sacituzumab govitecan in a patient with metastatic triple-negative breast cancer: a case report. J Med Case Rep. 2026;20:103.
- REMAP-CAP trial preliminary results: Oseltamivir in critically ill patients with influenza. 10 June 2026.
- Progestogen use and the risk of intracranial meningioma: a systematic review and meta-analysis. EClinicalMedicine. 2026 Feb;92:103791.
- Meningioma in users of progestogen contraceptives: a disproportionality analysis of the FDA Adverse Event Reporting System (FAERS). Eur J Clin Pharmacol. 2025.
