This document details the safety signals reviewed and the regulatory actions recommended by the European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) during its meeting in November 2025.
The key outcome is that the committee identified several potential safety issues requiring further investigation but did not recommend immediate label changes at this time. Instead, it has requested additional information from the marketing authorization holders (MAHs).
Summary of PRAC Recommendations
The table below outlines the specific drugs, safety signals, and required regulatory actions.
| INN (Active Substance) | Therapeutic Area / Use | Safety Signal (EPITT No.) | PRAC Recommendation & Deadline |
|---|---|---|---|
| Axicabtagene ciloleucel; Lisocabtagene maraleucel | CAR-T cell therapy for blood cancers | Increased risk of brain edema in patients with Primary Mediastinal Large B-cell Lymphoma (PMBCL) (20224) | Supplementary information requested from MAHs by 5 Feb 2026. |
| Ponatinib | Tyrosine kinase inhibitor for leukemia | Congenital megacolon (Hirschsprung’s disease) following maternal exposure during pregnancy (20231) | Supplementary information requested from MAH by 5 Feb 2026. |
| Valproate and related substances | Antiepileptic, mood stabilizer | Neurodevelopmental disorders in children following paternal exposure (20191) | Supplementary information requested from MAH by 11 Mar 2026. |
| Venlafaxine | Serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant | Cardiotoxicity (20230) | Supplementary information requested from MAH by 13 Apr 2026. |
| Desogestrel; Etonogestrel | Progestins (used in contraceptives, implants, IUDs) | Meningioma (20167) |
Detailed Medical & Pharmacovigilance Context
Here is a more detailed explanation of the medical significance behind each signal:
- CAR-T Therapies and Brain Edema: This signal highlights a potentially serious and specific risk for PMBCL patients receiving these cell therapies. Brain edema (cerebral edema) is a known but uncommon neurological toxicity of CAR-T therapy (often under the umbrella of Immune Effector Cell-Associated Neurotoxicity Syndrome, or ICANS). The PRAC is seeking more data to clarify if the risk is heightened in this particular lymphoma subtype.
- Ponatinib and Congenital Megacolon: This is a new potential teratogenic risk. Ponatinib’s label already contains strong warnings against use during pregnancy due to other risks. This signal suggests a possible link to Hirschsprung’s disease, a birth defect where nerves are missing in parts of the colon. The PRAC needs more case data to assess causality.
- Valproate and Paternal Exposure: This is a significant and novel signal. Valproate is a well-established, potent human teratogen with severe risks (neural tube defects, neurodevelopmental disorders) when taken by the mother during pregnancy. This investigation into paternal exposure (use by the father at the time of conception) explores a previously underexamined area. The PRAC is asking for data to investigate if the drug can affect sperm, potentially leading to disorders in offspring.
- Venlafaxine and Cardiotoxicity: While venlafaxine is known to have cardiovascular effects (like dose-dependent increases in blood pressure and heart rate), this signal prompts a fresh review of broader cardiotoxicity risks. The committee is likely examining cumulative post-marketing data on arrhythmias, QT prolongation, or other cardiac events.
- Progestins and Meningioma: This signal is directly related to previous discussion about Depo-Provera (medroxyprogesterone acetate). The PRAC is also monitoring other progestins (like desogestrel and etonogestrel) for a potential link to these brain tumors. The current decision of “No action” indicates that, while under watch, the evidence for these specific progestins is not yet sufficient to warrant label changes, unlike the recent FDA action on Depo-Provera.
Regulatory Implications
The request for “supplementary information” is a formal regulatory step. The MAHs must provide comprehensive data (e.g., detailed case analyses, literature reviews, clinical trial data reassessments) by the specified deadlines. Based on this information, the PRAC will decide if further regulatory action is needed, such as updating the Product Information (SmPC and package leaflet) with new warnings or contraindications.
