Gastrointestinal (GI) drugs represent one of the most widely prescribed therapeutic classes globally, encompassing proton pump inhibitors (PPIs), 5-aminosalicylates, anti-diarrhoeals, prokinetics, and the increasingly popular GLP-1 receptor agonists. The year 2025 witnessed a series of significant regulatory actions affecting the safety profiles of these medications, with implications for clinicians, patients, and pharmacovigilance systems worldwide.
Proton Pump Inhibitors (PPIs): Persistent Safety Concerns
Background
Proton pump inhibitors remain among the most frequently prescribed medications globally, used for gastro-oesophageal reflux disease (GORD), peptic ulcer disease, and as part of Helicobacter pylori eradication regimens. However, long-term use has been associated with multiple safety concerns that continued to attract regulatory attention throughout 2025.
Fracture Risk
The FDA has previously issued warnings regarding a possible increased fracture risk associated with PPI use. The mechanism is thought to involve reduced calcium absorption due to gastric acid suppression, leading to decreased bone mineral density. Patients at greatest risk include those taking prescription-strength formulations rather than over-the-counter products.
Clostridioides difficile Infection
Studies have demonstrated a ~1.7-fold increased risk of C. difficile-associated diarrhoea (CDAD) among PPI users. The FDA has issued warnings based on these findings, highlighting that PPIs are strongly linked to an increased risk of enteric infections. Clinicians should consider this risk when initiating or continuing PPI therapy, particularly in hospitalised patients or those with other risk factors for CDAD.
Potential Cancer Risks
A 2025 PLOS One study raised concerns regarding the increased risks of digestive system cancers associated with PPI use, including gastric, colorectal, pancreatic, oesophageal, and liver cancers, compared to H2-receptor antagonist (H2RA) use. While observational studies have limitations, the cumulative evidence warrants judicious prescribing and regular review of the ongoing need for PPI therapy.
FDA Actions Regarding Misbranding of Voquezna
In April 2025, the FDA determined that a video promoting Voquezna (vonoprazan), a potassium-competitive acid blocker (PCAB), was false or misleading and thus misbranded the product. This action underscores the FDA’s ongoing commitment to ensuring that promotional materials accurately reflect product safety and efficacy data.
Comparative Safety of Vonoprazan vs PPIs
A 2025 analysis querying the FDA Adverse Event Reporting System (FAERS) for adverse events reported for vonoprazan compared with the three most commonly used PPIs (pantoprazole, omeprazole, and esomeprazole) between 2023 and 2025 provided real-world safety data on this newer agent. The findings contribute to the evolving understanding of the safety profile of PCABs relative to traditional PPIs.
GLP-1 Receptor Agonists: Gastrointestinal Adverse Events Under Scrutiny
Background
GLP-1 receptor agonists (GLP-1 RAs), including semaglutide, liraglutide, and tirzepatide, have revolutionised the management of type 2 diabetes and obesity. However, their potent effects on gastric emptying and gastrointestinal motility have led to significant safety concerns that were the subject of multiple studies and regulatory reviews in 2025.
Common Gastrointestinal Adverse Effects
The most prevalent adverse effects associated with GLP-1 RAs include gastrointestinal disturbances, such as nausea, vomiting, diarrhoea, and constipation. While these are often transient and dose-dependent, they can be severe enough to cause treatment discontinuation.
Serious GI Complications
Large-scale cohort studies published in 2025 confirmed that the use of GLP-1 RAs for weight loss is associated with an increased risk of pancreatitis, gastroparesis, and bowel obstruction compared with the risks associated with bupropion-naltrexone. Genetically proxied GLP-1 RA use may increase the risk of acute pancreatitis.
Biliary Tract and Gallbladder Disease
A 2025 study of 369 type 2 diabetes patients followed for an average of 3.2 years found an increased risk of biliary duct and gallbladder diseases with GLP-1 RA use compared with other oral antidiabetic agents (adjusted hazard ratio 1.79, 95% CI 1.21-2.67). Clinicians should be vigilant for symptoms of biliary disease in patients on these agents.
Gastroesophageal Reflux Disease
A large real-world study of GI adverse events and all-cause mortality in GLP-1 RA-treated patients with type 2 diabetes found that patients treated with GLP-1 RAs had an increased risk of gastroparesis and GORD compared with those treated with SGLT-2 inhibitors. This is consistent with the known effects of GLP-1 RAs on gastric emptying.
Risk in Specific Populations
A 2025 systematic review and meta-analysis examining GLP-1 RA-associated adverse events in metabolic dysfunction-associated steatotic liver disease (MASLD) highlighted the importance of individualised risk assessment. Patients with pre-existing gastrointestinal conditions may be at higher risk of severe adverse effects.
Mesalamine and Other IBD Therapies
Mesalamine: Acute Intolerance Syndrome
Mesalamine (5-aminosalicylic acid) remains a cornerstone of inflammatory bowel disease (IBD) management. In 2025, FDA package inserts for multiple mesalamine products were updated to include prominent warnings about acute intolerance syndrome.
This syndrome, which may be difficult to distinguish from an exacerbation of ulcerative colitis, presents with:
- Cramping
- Acute abdominal pain
- Bloody diarrhoea
- Sometimes fever, headache, and rash
The exact frequency has not been determined, but it has occurred in 3% of patients in controlled clinical trials of mesalamine or sulfasalazine. Clinicians should be alert to this potential reaction, as it may lead to unnecessary escalation of IBD therapy if misdiagnosed as disease flare.
Mesalamine: Hepatic Failure and Hepatitis
A 2025 review of reports of hepatic failure and hepatitis associated with FDA-approved IBD therapies, including mesalamine, balsalazide, azathioprine, mercaptopurine, methotrexate, and tacrolimus, highlighted the importance of liver function monitoring in IBD patients.
Renal Considerations
FDA package inserts for mesalamine products continue to warn about use in patients with known renal impairment or a history of renal disease. Renal function should be monitored regularly in patients on long-term mesalamine therapy.
Upadacitinib (Rinvoq): Updated Indication and Safety Warnings
In October 2025, the FDA approved an updated indication statement for upadacitinib (Rinvoq) for the treatment of inflammatory bowel disease. However, the updated labelling includes prominent warnings about:
- Serious infections
- Increased risk of death in patients aged 50 years and older with at least one heart disease risk factor
- Cancers
- Major cardiovascular events
- Blood clots
- Allergic reactions
- Gastrointestinal tears
These warnings reflect the class effects of JAK inhibitors and underscore the need for careful patient selection and monitoring.
Mirikizumab (Omvoh): FDA Approval for Crohn’s Disease
In January 2025, the FDA approved mirikizumab-mrkz (mirikizumab) for the treatment of Crohn’s disease in adults. The FDA label includes warnings for hypersensitivity reactions, infections, tuberculosis, hepatotoxicity, and immunisations. This represents an important new therapeutic option but also necessitates pharmacovigilance to characterise its long-term safety profile.
CAR-T Cell Therapy: Immune-Mediated Enterocolitis
Background
Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionised the treatment of haematological malignancies. However, the 2025 safety signals from both the FDA and EMA highlighted a serious gastrointestinal toxicity associated with this class.
Immune Effector Cell-Associated Enterocolitis (IEC-EC)
In October 2025, the FDA added a label warning to Johnson & Johnson’s and Legend Biotech’s CAR-T therapy Carvykti (ciltacabtagene autoleucel) regarding a serious gut inflammation called immune effector cell-associated enterocolitis (IEC-EC). In some cases, this led to life-threatening complications, including bowel perforation and sepsis.
Patients may present with:
- Diarrhoea
- Stomach pain
- Weight loss
These symptoms often require intensive care and immune-suppressing drugs. The EMA’s PRAC also addressed this signal, noting that patients may develop immune-mediated enterocolitis, which may emerge several months after CARVYKTI infusion. There were events of gastrointestinal perforation, including fatal outcomes.
Clinical Implications
These safety signals have significant implications for oncology and gastroenterology practice. Clinicians managing patients post-CAR-T therapy should maintain a high index of suspicion for IEC-EC, even months after infusion. Early recognition and aggressive management are essential to prevent life-threatening complications.
Loperamide and Anti-Diarrhoeals
Cardiac Risks of Loperamide Overuse
Loperamide, a widely available over-the-counter anti-diarrhoeal, continued to attract regulatory attention in 2025. The FDA has issued repeated warnings regarding the cardiac risks associated with supratherapeutic doses of loperamide.
Cases of Torsades de Pointes, cardiac arrest, and death have been reported with the use of higher-than-recommended dosages of loperamide hydrochloride. The FDA’s labelling now includes prominent warnings:
- Heart alert: Taking more than directed can cause serious heart problems or death
- Allergy alert: Do not use if you have ever had a rash or other allergic reaction to loperamide HCl
Gastrointestinal Risks
Loperamide should not be used when inhibition of peristalsis is to be avoided due to the possible risk of significant sequelae, including ileus, megacolon, and toxic megacolon. If constipation, abdominal distention, or ileus develops, the drug should be discontinued.
Counterfeit Loperamide Warnings
In December 2025, the Philippine FDA issued a public health warning against the purchase and use of counterfeit versions of loperamide hydrochloride (Diatabs®) 2 mg capsules. This serves as a reminder of the global challenge of falsified medicines and the importance of sourcing medications from legitimate supply chains.
Domperidone: Ongoing PRAC Review
Domperidone, a dopamine antagonist used as an anti-emetic and prokinetic agent, has been subject to multiple safety reviews by the EMA’s PRAC over the years due to its association with QT prolongation and cardiac arrhythmias. In 2025, PRAC continued to review the benefit-risk balance of nationally authorised domperidone-containing medicines.
Clinicians should remain aware of the contraindications and precautions associated with domperidone, particularly in patients with cardiac risk factors or those taking other QT-prolonging medications.
WHO Alerts and Global Pharmacovigilance
Substandard Oral Liquid Medicines
In October 2025, the WHO issued a public alert regarding three substandard (contaminated) oral liquid medicines identified in India. These medicines were linked to localised clusters of acute illness and child fatalities. The toxic effects included:
- Abdominal pain
- Vomiting
- Diarrhoea
- Difficulty urinating
- Headache
- Altered mental state
- Acute kidney injury, which can result in death
This alert underscores the critical importance of pharmacovigilance and the role of WHO in detecting and responding to global drug safety threats.
WHO Model Lists of Essential Medicines
The updated WHO Model Lists of Essential Medicines (EML) and Essential Medicines for Children (EMLc) include several important therapies for high-burden diseases, including cancer, cystic fibrosis, haemophilia, and paediatric HIV with associated comorbidities.
Regulatory Framework and Signal Detection
PRAC Safety Signal Assessment
Throughout 2025, the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) systematically assessed safety signals for both centrally and nationally authorised medicinal products. The PRAC’s rigorous process ensures that only medicines meeting stringent safety criteria remain authorised.
Key PRAC meetings in 2025 addressed multiple safety signals, urging marketing authorisation holders to take immediate action to update product information and submit necessary variations. These updates included detailed descriptions of colitis symptoms such as watery diarrhoea and severe abdominal pain.
FDA Safety Labeling Changes
Throughout 2025, the FDA implemented multiple safety labeling changes for gastrointestinal drugs. These included:
- Updates to warnings and precautions sections regarding severe GI adverse reactions
- Revisions to acute pancreatitis warnings
- Updates to postmarketing experience sections
WHO VigiBase Analysis
A 2025 study published in the Journal of Pharmacoepidemiology and Risk Management evaluated the reporting patterns of lower gastrointestinal adverse events (LGI-AEs) associated with NSAID/PPI combination therapy compared with NSAID monotherapy and COX-2 selective inhibitors using VigiBase, the WHO global database of individual case safety reports. This analysis demonstrates the ongoing value of global pharmacovigilance databases in characterising drug safety profiles.
Clinical Implications and Practical Recommendations
For Proton Pump Inhibitors
| Recommendation | Rationale |
|---|---|
| Prescribe at the lowest effective dose for the shortest duration | Minimises risk of long-term adverse effects |
| Regularly review the ongoing need for PPI therapy | Many patients remain on PPIs without clear indication |
| Consider H2RAs or alternative therapies in patients at risk | Particularly in patients with osteoporosis or other risk factors |
| Counsel patients on potential risks | Including fracture risk, enteric infections, and potential cancer risk |
For GLP-1 Receptor Agonists
| Recommendation | Rationale |
|---|---|
| Start at the lowest dose and titrate slowly | Minimises GI adverse effects |
| Educate patients about GI side effects | Patients should be aware of expected and warning symptoms |
| Monitor for signs of pancreatitis, gastroparesis, and bowel obstruction | Early recognition is essential |
| Consider alternative therapies in patients with pre-existing GI conditions | Particularly in those with gastroparesis or a history of pancreatitis |
For Mesalamine and IBD Therapies
| Recommendation | Rationale |
|---|---|
| Be aware of acute intolerance syndrome | May mimic disease flare |
| Monitor renal function regularly | Mesalamine can cause renal impairment |
| Monitor liver function | Hepatotoxicity has been reported |
| Use JAK inhibitors and biologics with appropriate patient selection | Class effects include serious infections, cardiovascular events, and malignancy |
For Loperamide
| Recommendation | Rationale |
|---|---|
| Use only at recommended doses | Higher doses can cause cardiac arrhythmias |
| Counsel patients on cardiac risks | Particularly those with pre-existing cardiac conditions |
| Do not use when inhibition of peristalsis is contraindicated | Risk of ileus, megacolon, and toxic megacolon |
| Advise patients to report abdominal swelling or bulging | May indicate serious GI complication |
Conclusion
The year 2025 witnessed significant regulatory actions affecting the safety profiles of multiple gastrointestinal drug classes. From the persistent concerns surrounding PPIs and the emerging risks of GLP-1 receptor agonists, to the serious gastrointestinal toxicities of CAR-T therapy and the cardiac risks of loperamide overuse, the regulatory landscape for GI drugs continues to evolve.
Key takeaways for clinicians include:
- PPIs remain generally safe but should be prescribed at the lowest effective dose for the shortest duration, with regular review of ongoing need.
- GLP-1 receptor agonists offer substantial benefits but carry significant GI risks that require patient education and careful monitoring.
- Mesalamine can cause an acute intolerance syndrome that mimics disease flare, requiring careful diagnostic differentiation.
- CAR-T therapy is associated with immune-mediated enterocolitis that can emerge months after infusion and may be life-threatening.
- Loperamide overuse can cause serious cardiac arrhythmias, and counterfeit products pose additional risks.
- Pharmacovigilance systems, including VigiBase and national reporting schemes, remain essential for detecting and characterising drug safety signals.
The safety profile of any medication is not static; it evolves with accumulated real-world experience and scientific evidence. Clinicians, regulators, and patients share the responsibility of ensuring that the benefits of GI drugs continue to outweigh their risks through careful prescribing, monitoring, and reporting.
References
- U.S. Food and Drug Administration. FDA Drug Safety Communications. Various updates 2025.
- European Medicines Agency. PRAC recommendations on signals. Various meetings 2025.
- World Health Organization. WHO pharmacovigilance updates and alerts. 2025.
- PLOS One. Digestive system cancers and proton pump inhibitor use. 2025.
- FDA. Safety Labeling Changes for gastrointestinal products. Various dates 2025.
- FDA. Label warnings for Carvykti (ciltacabtagene autoleucel). October 2025.
- EMA. PRAC recommendations on Carvykti and immune-mediated enterocolitis. 2025.
- FDA. Warning regarding misbranding of Voquezna. April 2025.
- FDA Adverse Event Reporting System (FAERS). Comparative safety of vonoprazan vs PPIs. 2025.
- FDA. Upadacitinib (Rinvoq) updated indication and safety warnings. October 2025.
- FDA. Mirikizumab approval for Crohn’s disease. January 2025.
- DailyMed. Loperamide hydrochloride labelling updates. Various dates 2025.
- FDA Philippines. Counterfeit loperamide warnings. December 2025.
- WHO. Alert on substandard oral liquid medicines. October 2025.
- WHO Model Lists of Essential Medicines. 2025 update.
- WHO VigiBase. Lower gastrointestinal adverse events with NSAID/PPI combination therapy. 2025.
- Egyptian Drug Authority. EPVC Newsletters and safety communications. 2025-2026.
