What medications are associated with pancreatitis?

From the Guidelines

Medications such as azathioprine, GLP-1 receptor agonists, and DPP-4 inhibitors are associated with an increased risk of pancreatitis, and discontinuation of the offending medication is recommended if pancreatitis is suspected. Several medications are associated with pancreatitis, including certain antibiotics, diuretics, immunosuppressants, and antidiabetic drugs. Common culprits include azathioprine, 6-mercaptopurine, valproic acid, tetracyclines, furosemide, thiazide diuretics, estrogens, and glucagon-like peptide-1 (GLP-1) receptor agonists such as exenatide and liraglutide 1. Other medications linked to pancreatitis include ACE inhibitors, statins, NSAIDs, and certain HIV medications like didanosine. The risk varies by medication, with some having stronger associations than others. Drug-induced pancreatitis typically occurs through direct toxic effects on pancreatic cells, immunologic reactions, accumulation of toxic metabolites, or by causing pancreatic duct constriction. Symptoms usually develop within weeks to months after starting the medication but can sometimes occur after years of use.

Key Medications Associated with Pancreatitis

• Azathioprine: patients should be warned about the risk of pancreatitis and seek urgent medical attention if symptoms occur 1
• GLP-1 receptor agonists: acute pancreatitis has been reported, but causality has not been established, and discontinuation is recommended if pancreatitis is suspected 1
• DPP-4 inhibitors: pancreatitis has been reported, but causality has not been established, and discontinuation is recommended if pancreatitis is suspected 1 If pancreatitis is suspected, the offending medication should be discontinued immediately, and alternative treatments considered. The risk of recurrence is high if the same medication is reintroduced, so permanent discontinuation is often recommended for medications with strong associations to pancreatitis.

From the FDA Drug Label

The following adverse reactions are discussed in greater detail in other sections: Pancreatitis [see Boxed Warning, Warnings and Precautions (5.1)] In clinical trials using a buffered formulation of didanosine, pancreatitis resulting in death was observed in one patient who received didanosine plus stavudine plus nelfinavir, one patient who received didanosine plus stavudine plus indinavir, and 2 of 68 patients who received didanosine delayed-release capsules plus stavudine plus indinavir plus hydroxyurea Exocrine Gland Disorders - pancreatitis (including fatal cases) [see Warnings and Precautions (5.1)],

Medications associated with pancreatitis include:

• Didanosine: The drug label directly states that didanosine is associated with pancreatitis, including fatal cases 2. The frequency of pancreatitis is dose-related, with higher doses increasing the risk of this adverse reaction.

From the Research

Medications Associated with Pancreatitis

The following medications have been implicated in causing pancreatitis:

• Class I medications (medications implicated in greater than 20 reported cases of acute pancreatitis with at least one documented case following reexposure) include:
  • Didanosine
  • Asparaginase
  • Azathioprine
  • Valproic acid
  • Pentavalent antimonials
  • Pentamidine
  • Mercaptopurine
  • Mesalamine
  • Estrogen preparations
  • Opiates
  • Tetracycline
  • Cytarabine
  • Steroids
  • Trimethoprim/sulfamethoxazole
  • Sulfasalazine
  • Furosemide
  • Sulindac 3
• Class II medications (medications implicated in more than 10 cases of acute pancreatitis) include:
  • Rifampin
  • Lamivudine
  • Octreotide
  • Carbamazepine
  • Acetaminophen
  • Phenformin
  • Interferon alfa-2b
  • Enalapril
  • Hydrochlorothiazide
  • Cisplatin
  • Erythromycin
  • Cyclopenthiazide 3
• Other medications with a definite association with pancreatitis include:
  • Estrogens
  • Furosemide
  • Mercaptopurine
  • Pentamidine
  • Sulfonamides
  • Sulindac
  • Tetracyclines
  • Thiazides 4
• Medications with a probable association with pancreatitis include:
  • Cimetidine
  • Clozapine
  • Corticosteroids
  • Endoscopic retrograde cholangiopancreatography contrast media
  • Methyldopa
  • Metronidazole
  • Salicylates
  • Zalcitabine 4
• Valproic acid has been associated with acute pancreatitis, with a high fatality rate 5, 6

Mechanisms of Drug-Induced Pancreatitis

The mechanisms suggested for drug-induced pancreatitis include:

• Pancreatic duct constriction
• Immunosuppression
• Cytotoxic, osmotic, pressure, or metabolic effects
• Arteriolar thrombosis
• Direct cellular toxicity
• Hepatic involvement 4

Monitoring and Prevention

It is recommended to monitor patients receiving valproic acid therapy for the potential development of pancreatitis 5 Patients with a history of pancreatitis should be cautious when taking medications that have been associated with pancreatitis, and alternative treatments should be considered when possible 3, 4