What medications are associated with an increased risk of pancreatitis?

Medications Associated with Pancreatitis

Thiopurines (azathioprine and 6-mercaptopurine), GLP-1 receptor agonists, DPP-4 inhibitors, didanosine, valproic acid, and 5-ASA compounds are the most strongly associated medications with drug-induced pancreatitis. 1, 2

High-Risk Medications

Class I (Strongest Evidence)

• Didanosine (HIV medication): FDA label explicitly warns of fatal and nonfatal pancreatitis. Should be suspended in patients with signs or symptoms of pancreatitis and discontinued in confirmed cases 2
• Azathioprine and 6-mercaptopurine: Dose-independent pancreatitis occurs in approximately 4% of treated IBD patients, typically within 3-4 weeks of treatment initiation 1
• Valproic acid: Strong evidence from rechallenge cases 3, 4
• 5-ASA compounds (mesalamine, sulfasalazine): Associated with a 9-fold increased risk in recent users 5
• Estrogens: Documented in multiple case reports with positive rechallenge 3, 4
• Tetracycline: Multiple case reports support this association 3
• Opiates: Consistent reports of association 3
• Furosemide: Well-documented association 6, 3

Class II (Moderate Evidence)

• GLP-1 receptor agonists (semaglutide, dulaglutide, liraglutide): Acute pancreatitis has been reported, though causality not definitively established. Discontinue if pancreatitis is suspected 1
• DPP-4 inhibitors (sitagliptin, saxagliptin, alogliptin, linagliptin): Pancreatitis has been reported, discontinue if suspected 1
• Thiazide diuretics: Consistent association in multiple studies 6, 4
• ACE inhibitors: Multiple case reports suggest association 4
• Steroids: Multiple case reports document this association 3

Risk Factors for Drug-Induced Pancreatitis

• IBD patients: Higher risk with thiopurines, particularly in Crohn's disease 1
• HIV-positive patients: Higher risk with didanosine and other antiretrovirals 2, 3
• Genetic factors: Patients carrying the HLA-DQA102:01-HLA-DRB107:01 haplotype are more prone to thiopurine-induced pancreatitis 1
• Combination therapy: Particularly risky combinations include:
  • Thiopurines with stavudine 1
  • Didanosine with stavudine (especially in pregnant women) 2
  • Hydroxyurea with didanosine and stavudine (potentially fatal) 2

Clinical Presentation and Diagnosis

• Drug-induced pancreatitis typically presents similarly to other forms of acute pancreatitis 1
• Diagnosis requires at least two of three criteria:
  • Upper abdominal pain
  • Elevated serum lipase/amylase (>3x upper limit of normal)
  • Consistent abdominal imaging 1
• Timing is important - most drug-induced cases occur within days to weeks of starting the medication 3
• No unique clinical characteristics distinguish drug-induced from other causes of pancreatitis 7

Management Approach

1. Immediate discontinuation of the suspected medication 2, 7
2. Supportive care as with other forms of acute pancreatitis 1
3. Avoid rechallenge with the suspected agent unless absolutely necessary 3
4. Document the reaction in the patient's medical record to prevent future re-exposure 7

Prevention Strategies

• Careful monitoring during the first few weeks of therapy with high-risk medications, particularly thiopurines 1
• Avoid high-risk combinations (e.g., didanosine + stavudine, thiopurines + stavudine) 2
• Consider alternatives in patients with other risk factors for pancreatitis (gallstones, alcohol use) 1
• Educate patients about early symptoms of pancreatitis when prescribing high-risk medications 7

Special Considerations

• Incidence: Drug-induced pancreatitis accounts for approximately 0.1-2% of all acute pancreatitis cases 7
• Severity: While most cases are mild, severe and fatal cases can occur, particularly with didanosine 2
• Higher-risk populations: Children, elderly, patients with HIV, and those with inflammatory bowel disease have higher risk of drug-induced pancreatitis 3, 7