Drug-Induced Pancreatitis

Acute pancreatitis caused by an adverse reaction to a medicine, accounting for about 2 to 5% of acute pancreatitis (higher in children, patients with HIV, inflammatory bowel disease and cancer).

• Drugs with the strongest association: azathioprine and 6-mercaptopurine (about 3 to 5% of patients, usually within the first 1 to 2 months, idiosyncratic and not dose-related), valproate, didanosine and stavudine, asparaginase (2 to 18%, in children with leukaemia), mesalazine and sulfasalazine, oestrogens (through hypertriglyceridaemia), tamoxifen, tetracyclines, metronidazole, furosemide and thiazides, angiotensin converting enzyme inhibitors, simvastatin, carbamazepine, codeine and other opioids, trimethoprim-sulfamethoxazole, 5-aminosalicylates, oestrogen, pentamidine, protease inhibitors, and propofol.
• Drugs with a possible link: glucagon-like peptide 1 agonists, dipeptidyl peptidase 4 inhibitors (association uncertain), checkpoint inhibitors, and some herbal products.
• Mechanisms: immune hypersensitivity, direct toxicity (intracellular metabolite accumulation), hypertriglyceridaemia, hypercalcaemia, pancreatic duct constriction (opioids), and vasculitis.
• Diagnosis rests on timing, exclusion of other causes, improvement after withdrawal, and recurrence on re-exposure; mortality is low (less than 5%), with most cases mild.

Epigastric pain, nausea and vomiting, usually within days to weeks of starting a drug (azathioprine within 4 weeks; valproate within months; asparaginase within 2 weeks), occasionally after years of use.

• Fever, rash and eosinophilia in hypersensitivity forms; features of the underlying disease (Crohn disease, ulcerative colitis, epilepsy, HIV, leukaemia).
• Mild disease is typical, with some severe cases (valproate, didanosine, asparaginase).
• Differential diagnosis: gallstone, alcohol and hypertriglyceridaemic pancreatitis, underlying disease related pancreatitis (Crohn disease), infection (mumps, cytomegalovirus), hypercalcaemia, autoimmune pancreatitis, tumour, and biliary disease.
• Complications: those of acute pancreatitis (necrosis, pseudocyst, organ failure), recurrence on re-exposure (often more severe), and rarely chronic pancreatitis.

Lipase of more than 3 times normal with typical pain, after exclusion of other causes (ultrasound for gallstones, triglycerides, calcium, alcohol history, viral serology if indicated, CT or MRCP for tumour and structural disease).

• Medication history with timing of start and any recent dose changes; review of all prescribed, over-the-counter and herbal products.
• Features favouring drug causation: onset after a new drug, no other cause, resolution within days after stopping, and recurrence on re-exposure (avoid deliberate rechallenge).
• Drug level monitoring where relevant (valproate level, thiopurine metabolites, triglycerides during oestrogen or propofol use).
• Check eosinophilia, liver tests, and IgG4 for autoimmune disease if atypical.
• Report the reaction to the national pharmacovigilance centre.

Stop the suspected drug immediately (and avoid all drugs in the same class when a class effect is likely), and document the reaction as an allergy or intolerance in the record; do not rechallenge.

• Supportive care:
  • Lactated Ringer solution 5 to 10 mL/kg/hour for 12 to 24 hours, with reassessment every 6 hours (urine output more than 0.5 mL/kg/hour, mean arterial pressure 65 to 85 mmHg).
  • Paracetamol 1 g every 6 hours, with morphine 2 to 5 mg IV every 2 to 4 hours as needed, or fentanyl 25 to 50 micrograms IV; avoid opioids as the cause when pancreatitis follows opioid use.
  • Oral low fat feeding as soon as pain allows, or enteral feeding by tube if intake fails by 48 to 72 hours.
  • No prophylactic antibiotics; enoxaparin 40 mg SC daily; oxygen; critical care for organ failure.
• Alternatives to the stopped drug, chosen with the prescriber:
  • Azathioprine or mercaptopurine: use methotrexate 15 to 25 mg weekly with folic acid 5 mg weekly, or a biologic such as infliximab 5 mg/kg IV at weeks 0, 2 and 6 then every 8 weeks, adalimumab 160 mg then 80 mg then 40 mg every 2 weeks, or vedolizumab 300 mg IV at weeks 0, 2 and 6 then every 8 weeks, in inflammatory bowel disease.
  • Valproate: change to levetiracetam 250 mg twice daily increasing to 500 to 1500 mg twice daily, or lamotrigine titrated slowly, with a cross-taper over 2 to 4 weeks (stop valproate gradually unless life-threatening).
  • Didanosine or stavudine: switch to tenofovir with emtricitabine and dolutegravir 50 mg daily (adjust with rifampicin).
  • Mesalazine: switch to another 5-aminosalicylate or other therapy for colitis, with specialist advice.
  • Asparaginase: do not rechallenge after severe pancreatitis; discuss alternative regimens with the oncology team.
  • Ooestrogen, tamoxifen, or propofol: use progestogen-only or non-hormonal options, an alternative anaesthetic or sedative, and manage triglycerides with insulin if raised.
  • Furosemide or thiazide: replace with an agent of another class (amlodipine 5 to 10 mg daily for hypertension).
  • Opioid: stop and use non-opioid analgesia.
• Severe disease or complications: give critical care for organ failure, lactated Ringer solution 5 to 10 mL/kg/hour, analgesia and enteral nutrition, drain infected or obstructing collections after 4 weeks, and give meropenem 1 g IV every 8 hours for infected necrosis.
• Special groups: children (leukaemia treatment with asparaginase needs oncology planning; valproate alternatives; fluids at 1.5 to 2 times maintenance); pregnancy (stop the drug and use pregnancy-safe alternatives, for example levetiracetam for epilepsy, with supportive care); elderly (polypharmacy review); renal impairment (adjust antibiotics, avoid NSAIDs); HIV (antiretroviral switch with specialist input); immunosuppression and cancer (shared decisions with the specialist team).
• Red flags: persistent pain beyond 72 hours after withdrawal, organ failure, necrosis, severe hypertriglyceridaemia, recurrent episodes on a different drug, alcohol or gallstone coexisting.
• Follow-up: clinical and lipase review at 1 to 2 weeks; repeat imaging at 6 weeks if collections; record the drug as a contraindication; review the primary disease treatment with the specialist; check glucose and exocrine function if severe disease.