DRUG INDUCED ACUTE PANCREATITIS : RESULT FROM THE HOSPITAL-BASED

BERLIN CASE CONTROL SURVEILLANCE STUDY OF 102 CASE

A.Douros, E.Bronder, F.Andersohn, et all

Alimentary Pharmacology and Therapeutics

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DRUG TOXICITY common cause of non alcoholic ACUTE PANCREATITIS

> 500 drugs, Various classes

Spontaneous reporting reports and published case control

Valuable source to provide signal of drug risk

INTRODUCTION

METHODS

The hospital-based Berlin case control survellance study FAKOS

Initiated in 2000 serious toxic of drugs

Comprised > 180 department of Internal Medicine,Neurology,Psychiatri, and Anaesthesiology

Of all 51 Berlin Hospital

October 2002 – December 2011

CASE IDENTIFICATION AND RECRUITMENT

Case identified study centre

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reported

Trained member of

FAKOS

• obtained informed consent• Face to face interview • Collecting on all previous drug intakes• Co-morbidity• Other possible risk factor e.g chemicals,solvent or smoking

METHODS

the standardised questionnaire first asked the control and case for previous and current

Disease and for the drugs taken for the disease

The study region was in Berlin, with 2.8 million adult inhabitants as source population

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METHODS

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METHODS

INCLUDED CRITERIA • minimum age of 18 years • a new diagnosis of IAP within the last 6 months • at least 2 of the following 3 criteria ; elevation of lipase or amylase at least threefold above ULN, characteristic upper abdominal pain or signs of pancreatitis in imaging

EXCLUDED CRITERIA

• Chronic pancreatitis• Biliary etiology icl. Choledocholitiasis • Prior history of biliary colic• Dilated biliary tract or concomitant rise of transminase and bilirubin • Other obstruction-related etiology of AP such as pancreatic tumor or pancreatic malformations• Alcoholic • Ischaemic trauma induced AP• Hyperparathyroid• Massive hypertriglyceridaemia ( > 11.2 mmol/L)• ERCP in the last 48 hours

IAP was validated as certain, propable,possible, or unlikely based on clinical information about laboratory and other diagnostic test

The grading of pancreatitis was based on imaging findings

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METHODS

Case validation and characterisaton

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METHODS

Control selection •Conducted from january 2002 – december 2011 at the same hospital where case were recruited

• the aim to raise a multiple of controls compared with cases to increase study power

•The control/case ratio was approximately 7:1

•Informed consent was obtain and control patients were subsequently interviewed in the same standarised way as the IAP patients

• the index date was defined as the date of hospitalitation or date of the onset of the control disease if this preceded hospitalitation

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A drug reaction was evaluated as “certain”

A clinically reasonable response on drug withdrawal (“possitive dechallenge”) was observed

AP was observed on re-exposure to the same drug (“positive rechallenge”)

The causality “was propable” when AP occured with a reasonable time sequence to the drug administration and not attributed to other causes

the drug reaction was possible when there was a plausible time sequence to drug intake

Standardised assessment of drug causality in individual cases

METHODS

Included all cases validated as certain or probable irrespective of the result of causality assessment

out patient case & control were considered as exposed to drug if the drug had taken in last 7 days before the index time

Odds ratio (OR) and 95% confidence interval (CI) of IAP associated with exposure to spesific drug , calculated by logistic regression analysis

all risk calculatioon were performed by SAS statistical software

a two tailed P value < 0.05 was considered significant

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METHODS

Case control analysis

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RESULTS

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RESULTS

Drug causality assessment in

individual casesAP

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RESULTS

Case Controlanalysis

Show the characteristic of out-patient

cases,including grading of AP, associated

laboratory findings and clinical symptom,

complication,imaging findings and outcome

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RESULTS

associated?Lancashire et al using GRPD :

“ a few drug commonly reported as suspected to cause AP either did’nt have an increased at all ( statin) or did’nt have an increased risk compared with other, more seldom reported drugs of the same class ( valproic acid )

risk

azathioprine, mesalazine, mercaptopurin , ACE Inhibitor, fenofibrat and leflunomide ( RARE )

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DISCUSSION

500 drugs AP

Case control analysis

This study corroborate previous findings that suggest an absence of fixed duration of drug use in DIAP

The thiopurines azathioprine and mercaptopurin as well as dervative of salysilic acid mesalazine, have been repeatedly reported AP

a positive rechallenge was doumented, and therefore a certain causality was indicated

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DISCUSSION

Potentialpancreatotoxic

herbal Harpagophytum and valerian radix as well as for tocilizumab

probable

relation

not significant

However, as biliary sludge depicts as idiopathic, this remains a potential limitation to this study

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DISCUSSION

Cefouraxim, cefotaxime, and cefixime AP ceftriaxone

DM,Smokers AP

not narowing it’s focus to spesific drugs

able to assess a wide range of drug

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DISCUSSION

FAKOS

Participated by

Hospital and medical

department

In case of characteristic abdominal pain or an elevation of the respective laboratory parameters, drugs should be part of the differential diagnosis, especially when alcohol

intake or gallstone can be ruled out as posible causes

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