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 cases
AP
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RESULTS
Case
Control
analysis
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 didnt have an
increased at all ( statin) or didnt 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
Potential
pancreatotoxic
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 its 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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