REVIEW
Drug-Induced Acute Pancreatitis in Adults
An Update
C. Roberto Simons-Linares, MD, MSc,* Mohamed A. Elkhouly, MD,† and Miguel J. Salazar, MD†
Abstract: Drug-induced acute pancreatitis (DIAP) is a rare entity that is
often challenging for clinicians. The aim of our study was to provide up-
dated DIAP classes considering the updated definition of acute pancreatitis
(AP) and in light of new medications and new case reports. A MEDLINE
search (1950–2018) of the English language literature was performed
looking for all adult (≥17 years old) human case reports with medication/
drug induced as the cause of AP. The included case reports were required
to provide the name of the drug, and diagnosis of AP must have been strictly
established based on the revised Atlanta Classification criteria. A total of 183
medications were found to be implicated in 577 DIAP cases. A total of 78
cases were excluded because of minimal details or lack of definite diagnosis
of AP. Drug-induced AP is rare, and most drugs cause mild DIAP. Only 2
drugs are well described in the literature to explain causation rather than as-
sociation (azathioprine and didanosine). Larger case-control studies and a
formal standardized DIAP reporting system are essential to study the true po-
tential of the DIAP-implicated drugs described in this review.
Key Words: acute pancreatitis, cannabis pancreatitis,
drug-induced pancreatitis, mechanism pancreatitis, medication pancreatitis
(Pancreas 2019;48: 1263–1273)
A cute pancreatitis (AP) is one of the most common diseases of
the gastrointestinal tract with annual incidence of about 87.7
cases per 100,000 and results in about 275,000 annual hospital ad-
missions in the United States with increased associated costs.1 Al-
though gallstones and alcohol are responsible for more than 80%
of all cases in adults, medications have been recognized as a po-
tential cause of AP.2
Drug-induced AP (DIAP) is a rare entity that often is chal-
lenging for clinicians. There are more than 120 drugs that have
been implicated in causing AP with different mechanism of injury
reported in the literature.3 In addition, the World Health Organiza-
tion database has listed more than 500 drugs that could cause AP
as an adverse effect.4 In 1975, Karch and Lasagna5 proposed
criteria to evaluate the probability of an adverse drug reaction to
be caused by a specific suspected drug. Later in 2007, Badalov
et al2,3 classified medications-based weight of evidence for each
agent and pattern in presentation to 5 classes, but from 2007,
new medications had evolved, and AP definition changed based
on the Revised Atlanta Classification criteria.
From the *Digestive Disease Institute, Gastroenterology and Hepatology De-
partment, Cleveland Clinic, Cleveland, OH; and †Internal Medicine Depart-
ment, Cook County Health, Chicago, IL.
Received for publication December 19, 2018; accepted September 19, 2019.
Address correspondence to: Carlos Roberto Simons-Linares, MD, MSc,
Digestive Disease Institute, Gastroenterology and Hepatology Department,
Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195
(e‐mail: robertosimons@outlook.com).
The authors declare no conflict of interest.
Supplemental digital contents are available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions
of this article on the journal’s Web site (www.pancreasjournal.com).
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/MPA.0000000000001428
Pancreas • Volume 48, Number 10, November/December 2019
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
The aim of our study was to provide updated DIAP classes
considering the updated definition of AP and in light of new med-
ications and new case reports.
MATERIALS AND METHODS
Identification of Culprit Drugs
A MEDLINE search (1950–2018) of the English language
literature was performed looking for all adult (≥17 years old) hu-
man case reports with medication/drug induced as the cause of
AP. Search terms included “drug induced” or “medication in-
duced” or “drug” or “medications” combined with “pancreatitis.”
The latest search date was September 30, 2018. Pharmaceutical
and Food and Drug Administration data were not used for
this analysis.
All published case reports were reviewed by 2 physicians (M.
A.E. and M.J.S.). The included case reports were required to pro-
vide the name of the drug, and diagnosis of AP must have been
strictly established based on revised Atlanta Classification
criteria2: by clinical symptoms, increase of the amylase and/or li-
pase level greater than 3 times the upper limit of normal (ULN),
and/or computed tomography (CT) or ultrasound findings consis-
tent with AP. Pancreatitis evident on autopsy or laparotomy was
considered as a positive finding even if other symptoms, labora-
tory, or imaging were missing.
If the case mentioned that the patient had pancreatitis in the
past with no details, no rechallenge was considered; all details of
initial and recurrent attacks were needed. Although most of the
case reports were published in medical literature, letters that pro-
vided enough information, as above, were also included.
Case reports with minimal data, those that failed to fulfill AP
definition, or those that were written in language other than En-
glish were excluded.
Classification of Culprit Drugs
Drugs that fulfilled the above inclusion criteria were classi-
fied into probability groups based on a classification used by
Badalov et al3 (Table 1). Class Ia drugs included drugs with at
least 1 case report with positive rechallenge, excluding all other
causes, such as alcohol, hypertriglyceridemia, gallstones, and
other drugs. Class Ib drugs included drugs with at least 1 case re-
port with positive rechallenge; however, the case report failed to
document exclusion of other causes or other possible etiologies
were available. Class II drugs included drugs that had at least 4
cases in the literature with consistent latency. Class III drugs in-
cluded at least 2 cases in the literature with no consistent latency
among cases and no rechallenge. Class IV drugs included drugs
not fitting into the earlier described classes, single case report pub-
lished in medical literature, without rechallenge.
Latencies were classified to short (latency of <24 hours),
intermediate (latency of 1–30 days), and long (latency >30 days).3
Time to onset was determined as the time from intake of the
medications until pancreatitis was confirmed by laboratory or
imaging modalities.
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Simons-Linares et al
TABLE 1. Classification Method of Culprit Drugs
Class Ia
• At least 1 case report with positive rechallenge
• Excluding all other causes, such as alcohol, hypertriglyceridemia,
gallstones, and other drugs
Class Ib
• At least 1 case report with positive rechallenge
• Case report failed to document exclusion of other causes or
• Other possible etiologies were available
Class II
• At least 4 cases in the literature with consistent latency*
Class III
• At least 2 cases in the literature with no consistent latency among
cases and no rechallenge
Class IV
• Drugs not fitting into the earlier described classes
• Single case report published in medical literature, without
rechallenge
*Latencies were classified into short (latency of <24 hours), intermedi-
ate (latency of 1–30 days), and long (latency >30 days).
Determination of the Type of Pancreatitis
Type of AP was either interstitial edematous or necrotizing
based on CT of the abdomen or abdominal ultrasound findings
and in relation to the Revised Atlanta Classification criteria.2 Type
of pancreatitis was documented as “unknown” if no CT of the
abdomen or ultrasound was done. Pancreatitis type was consid-
ered as edematous if CT of the abdomen was done but no signs
of AP were found.
Determination of the Severity of Pancreatitis
Severity of AP was classified into mild, moderately severe,
and severe, based on the Revised Atlanta Classification.2 Mild
AP was characterized by absence of organ failure or local or sys-
temic complications. Moderately severe pancreatitis was charac-
terized by presence of local complication or transient organ
failure <48 hours. Severe AP was characterized by persistent or-
gan failure >48 hours. Organ failure was defined using the modi-
fied Marshall scoring system.6
Local complications were defined as presence of acute
peripancreatic fluid collection, pancreatic pseudocyst, acute ne-
crotic collection, or walled-off necrosis on abdominal ultrasound
or CT of the abdomen. Systemic complication was defined as ex-
acerbation of preexisting comorbidity, such as coronary artery dis-
ease or chronic lung disease, precipitated by the AP. If no organ
failure or local complications were mentioned in the case report,
the pancreatitis was considered as mild AP.2
Naranjo Score and Other Causes
We calculated the Naranjo score for all the case reports,
which is a subjective way to determine the likelihood of an ad-
verse drug reaction. Probability was assigned via a score termed
definite (≥9), probable (5–8), possible (1–4), or doubtful (≤0).7
Other causes of exclusion including alcohol intake, gall-
stones, and hypercalcemia were documented in a separate col-
umn. Hypertriglyceridemia secondary to medications causing
AP was present in some cases and in this situation was not
considered as a cause that needed to be excluded, and the drug
could have been classified as class Ia.
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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 48, Number 10, November/December 2019
In cases that involve multiple medications that can cause AP,
other medications were not considered as an etiology of the
pancreatitis if the other medications were continued after re-
moval of the culprit drug with no further attacks. If other causes
were not mentioned, the article would receive “no” for exclu-
sion of other causes.
RESULTS
A total of 183 medications were found to be implicated in AP
secondary to drugs in a total of 577 cases, summarized in Table 2
and Supplemental Digital Content 1 (Supplemental Tables 1A–D),
http://links.lww.com/MPA/A745. A total of 78 cases were excluded
because of minimal details or lack of definite diagnosis of AP, sum-
marized in Supplemental Digital Content 2, http://links.lww.com/
MPA/A746.
Class Ia
A total of 32 medications had at least 1 case report with
positive rechallenge, excluding all other causes, such as alcohol,
hypertriglyceridemia, gallstones, and other drugs. These drugs
are acetaminophen, acetaminophen-codeine, 5-aminosalicylate,
amiodarone, androgenic anabolic steroids, arsenic trioxide, can-
nabis, carbimazole, cimetidine, clomiphene, enalapril, estrogen
and related products, furosemide, in vitro fertilization, isoniazid,
losartan, α-methyldopa, metronidazole, nadolol, pravastatin,
perindopril, procainamide, pyritinol, ranitidine, rosuvastatin,
saxagliptin, simvastatin, sulindac, tamoxifen, telaprevir, tetracy-
cline, and trimethoprim/sulfamethoxazole. See Supplemental
Digital Content 3, http://links.lww.com/MPA/A747, for a com-
plete list of case references.
Acetaminophen
Acetaminophen was documented as the cause of AP in a to-
tal of 9 cases, most secondary to overdose or suicidal attempt.
Igarashi et al8 described a case of severe AP in a female patient
that occurred 1 month after taking about 5.3 to 10.6 g of acetamin-
ophen daily for pain control with positive rechallenge after 1 week.
Death was reported in 1 case report,9 and moderate to severe pan-
creatitis was reported in 5 cases.
Acetaminophen-Codeine
Both acetaminophen and codeine had been reported alone as
a cause of DIAP, but 4 case reports described AP in patients using
a combination of both medications, which makes it difficult to dif-
ferentiate which of them is the culprit medication; perhaps both
medications have a combined effect, causing AP.10–12 Hastier
et al11 described mild pancreatitis 90 minutes after taking acet-
aminophen for abdominal pain with positive rechallenge after
1 hour. All cases had mild pancreatitis with favorable outcome.
5-Aminosalicylate
Different 5-aminosalcylate compounds, including mesalamine,
both oral and rectal13 preparations, and sulfasalazine.14,15 All de-
scribed patients had mild pancreatitis with favorable outcome. Four
case reports were excluded from final analysis because of minimal
data and lack of AP definition.
Amiodarone
Bosch and Bernadich described AP after 4 days of receiving
amiodarone for atrial fibrillation with positive rechallenge after
3 days.16 All reported cases showed favorable outcome with only
mild pancreatitis. One case report described by Sastri et al17 was ex-
cluded because of amylase and lipase elevation less than 3 ULN.
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Pancreas • Volume 48, Number 10, November/December 2019 Drug-Induced Acute Pancreatitis

TABLE 2. Classification of Implicated Medications

Class Ia Class Ib Class II Class III Class IV

Acetaminophen Azathioprine All-trans retinoic acid Aspirin L-Arginine Interferon β1a
Acetaminophen- Bortezomib L-Asparaginase/peg Atorvastatin Adefovir Interleukin 2
codeine Carbamazepine asparaginase Capecitabine Ado-traztuzumab emtansine Ketoprofen
5-Aminosalicylate Clonidine Canagliflozin Captopril Albiglutide Lacosamide
Amiodarone Clozapine Chlorothiazide Ceftriaxone Allopurinol Lamivudine
Androgenic Anabolic Cytosine arabinoside Codeine Celecoxib Amitriptyline Lamotrigine
steroids Dapsone Dideoxy inosine Chlorthalidone Amoxicillin/clavulanate Lanreotide autogel
Arsenic trioxide Dexamethasone Gold therapy Ciprofloxacin Ampicillin Levetiracetam
Cannabis Fenofibrate Hydrochlorothiazide Clarithromycin Anagrelide hydrochloride Mefenamic acid
Carbimazole Hydrocortisone Interferon α2b/ribavirin Cocaine Artesunate Micafungin sodium
Cimetidine 6-Mercaptopurine Lisinopril Cyclosporine Atenolol Miltefosine
Clomiphene Methimazole Liraglutide Doxycycline Axitinib Montelukast
Enalapril Mirtazapine Meglumine antimonate Erythromycin Benazepril Motesanib
Estrogen and related Nelfinavir Nilotinib Everolimus Bendroflumethiazide Mycophenolate mofetil
products Nitrofurantoin Olanzapine Exenatide Bezafibrate Naltrexone
Furosemide Omeprazole Prednisolone Indomethacin Boceprevir Nifuroxazide
In vitro fertilization Paclitaxel Riluzole Interferon α2b Brentuximab vendontin Nivolumab
Isoniazid Pentamidine Sitagliptin Irbesartan Calcium carbonate Octreotide
Losartan Prednisone Ketorolac C. kondoi Oxacalcitriol
Methyldopa Propofol Metformin Danazol Oxyphenbutazone
Metronidazole Quetiapine Metolazone Diclofenac Paromomycin
Nadolol Sodium stibogluconate Minocycline Dideoxycytidine Phenolphthalein
Pravastatin Sorafenib Naproxen Dimethyl fumarate Ramipril
Perindopril Tigecycline Orlistat Entecavir Risperidone
Procainamide Valproic acid Pazopanib Ergotamine tartrate Roxithromycin
Pyritinol Valsartan Phenformin Estramustine phosphate Secnidazole
Ranitidine Ritonavir Ethacrynic acid Sertraline
Rosuvastatin Saw palmetto Ezetimibe Stavudine
Saxagliptin Tacrolimus Famciclovir Sunitinib
Simvastatin Vildagliptin Fluconazole Tacalcitol
Sulindac Fluvastatin Telmisartan
Tamoxifen Gadobenate dimeglumine Theophylline
Telaprevir (Multihance) Tinidazole
Tetracycline Glimepiride Tocilizumab
Trimethoprim/ Horsetail infusions Vedolizumab
sulfamethoxazole (E. arvense) Vemurafenib
Ibuprofen Venlafaxine
Icodextrin Vinblastine
Ifosfamide Ziprasidone
Imatinib
Interferon α2a

Androgenic Anabolic Steroids
The use of androgenic anabolic steroids as performance-
enhancing drugs has increased recently among young athletes.18
Kumar et al19 described recurrent pancreatitis with trenbolone ace-
tate. Liane et al20 in addition to Rosenfeld et al21, described cases of
other steroids types, with severe pancreatitis in one of them.
Arsenic Trioxide
Connelly et al22 described recurrent AP in a patient receiving
arsenic trioxide for acute promyelocytic myelogenous leukemia,
with exclusion of all other possible pancreatitis etiologies. Hantson
et al23 described another case of AP in patient, likely secondary to
criminal intoxication, but the case was excluded from final analysis
because of lack of characteristic abdominal pain or supportive im-
aging findings of AP.
Cannabis
Cannabis is currently one of the most frequently consumed
recreational drug in the world.24 Literature review revealed a total
of 11 case reports of cannabis-induced AP, with positive rechal-
lenge in 3 patients.25–27 One case report was excluded because
of limited details. In a systematic review, cannabis was found to
be a possible risk factor for AP and recurrent AP.28
On the other hand, a cohort study from a large tertiary center
that included 460 patients with a first episode of AP studied the
impact of cannabis in AP. The authors did not find any case
of cannabis that directly induced AP. However, 9% of so-called

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Simons-Linares et al
idiopathic cases in this cohort were cannabis users, which
could account as an association for approximately 2% of all AP
cases. Finally, cannabis did not independently impact the severity
of AP.29
Carbimazole
Carbimazole used in Graves disease has been associated with
acute mild pancreatitis in 2 case reports with favorable outcomes.30,31
Marazuela et al31 described a case of AP in a 33-year-old woman
with recurrence after only 1 day.
Cimetidine and Ranitidine
Cimetidine was reported as a probable cause of AP in a total
of 5 cases. Wilkinson et al32 described 2 case reports with positive
rechallenge, where other possible causes of pancreatitis were ex-
cluded in one of them. All the patients had mild pancreatitis with
favorable outcome, apart from 1 case report that described a pa-
tient with severe AP who died after 18 days of hospitalization
due to sepsis.33 A case described by Nott and De Sousa34 was ex-
cluded because of absence of characteristic epigastric pain. Ranit-
idine, another H2 blocker, has also been implicated in DIAP with
positive rechallenge.35
Clomiphene
Clomiphene is a nonsteroidal estrogen analog of the
triphenylethylene derivative group and has been used to treat women
with certain anovulatory disorders.36 Three case reports had implicated
clomiphene as a cause of AP. Hypertriglyceridemia was the likely
mechanism of pancreatitis in 2 patients,37 but Keskin et al38 described
a case of recurrent pancreatitis with normal triglyceride level.
Enalapril and Perindopril
Carnovale et al39 described a case of recurrent AP in a patient
receiving enalapril for blood pressure control with positive rechal-
lenge after 10 days. Literature review revealed other 8 cases of
mild/moderate pancreatitis with favorable outcome, apart from a
case reported by González Ramallo et al40 of severe pancreatitis
with death as the final outcome. Gallego-Rojo et al41 described
mild pancreatitis associated with perindopril, another angiotensin-
converting enzyme inhibitor with favorable outcome. Two case re-
ports associated with enalapril were excluded because of lack of
clear AP diagnosis.
Estrogen and Related Products
Acute pancreatitis secondary to exogenous estrogen exposure
has been described in many forms. Two cases of AP with favorable
outcomes were reported, after exposure to estradiol valerate in
preparation to cryo-thawed embryo transfer.33,42 Further
cases were described after exposure to oral contraceptive
pills, estrogen replacement therapy, and in preparation of gen-
der reassignment surgery. Hypertriglyceridemia was likely
the main mechanism of AP,37 but in 3 case reports, AP occurred
in light of normal lipids.43–45 A total of 5 case reports were ex-
cluded from final analysis.
Furosemide
Furosemide was incriminated in 7 cases of AP, with positive
rechallenge in 4 cases. Hypertriglyceridemia was reported as a
probable mechanism of pancreatitis in a patient receiving furose-
mide daily for hypertension.46 Patient was also taking estrogen
replacement therapy for menopausal symptoms, which can also
cause hypertriglyceridemia. The patient was rechallenged by fu-
rosemide and estrogen separately to point out the offending drug.
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Pancreas • Volume 48, Number 10, November/December 2019
Acute pancreatitis occurred only after 3 days of exposure to fu-
rosemide but with no evident hypertriglyceridemia.45 Three
cases reported by Buchanan and Cane47 were excluded due to
limited data.
In Vitro Fertilization
Steinmetz et al48 and Aljenedil et al,49 described 2 cases of
AP after in vitro fertilization cycle with positive rechallenge af-
ter the second cycle in one of the cases, both with favorable out-
comes. In both cases, hypertriglyceridemia was likely the main
mechanism of AP.
Isoniazid
Isoniazid was associated with pancreatitis in multiple pa-
tients, either during chemoprophylaxis or treatment of tubercu-
losis. Positive rechallenge was described in a total of 6 patients,
with exclusion of other causes in 4 patients. Kvale and Parks50
described a case of acute abdomen in 1975 related to isoniazid,
but it was excluded because of lack of other confirmatory tests
and imaging.
Losartan
Birck et al51 and Bosch52 described 2 patients with mild AP
with favorable outcome after receiving 50 mg of losartan daily for
treatment of hypertension, one after 1 week and the other after
5 months with positive rechallenge.
α-Methyldopa
Van der Heide53 et al and Rominger et al54 also described
2 patients with mild pancreatitis after receiving α-Methyldopa
for hypertension with positive rechallenge. Another case de-
scribed by Van der Heide et al53 in addition to a case described
by Warren et al55 were excluded because of absence of abdominal
pain or confirmatory imaging studies.
Metronidazole
Multiple case reports implicated metronidazole in AP, with pos-
itive rechallenge in 3 patients,56–58 and all with favorable outcome.
Nadolol
O'Donoghue59 described a case of mild AP after receiving
4 weeks of nadolol, secondary to hypertriglycemia with positive
rechallenge after 10 days.37 The rise in the concentration of serum
triglycerides in β-blockers could be secondary to impaired triglyc-
erides catabolism, because β-blockade was associated with reduced
endothelial lipoprotein lipase activity secondary to unopposed α-
adrenergic stimulation.60
Statins
Paravastatin,61,62 rosuvastatin,63,64 and simvastatin65–69 have
all been involved in AP, with positive rechallenge. Atorvastatin
(class III) and fluvastatin (class IV) are also other statins that have
also been implicated with DIAP.
Procainamide
Falko and Thomas70 described DIAP in a patient taking pro-
cainamide for 7 months with positive rechallenge after 3 to 4 weeks
and with favorable outcome. The patient had also other manifesta-
tions of procainamide-induced lupus erythematosus.
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Pancreas • Volume 48, Number 10, November/December 2019
Pyritinol
Pyritinol, semisynthetic water-soluble analog of vitamin B6,
was associated with DIAP described by Straumann et al71 with
positive rechallenge 3 times.
Saxagliptin
Saxagliptin, a dipeptidyl peptidase-4 inhibitor, was also
associated with DIAP in 1 case described by Lee et al72 with
favorable outcome.
Sulindac
Multiple reports have implicated sulindac with mild DIAP,
with positive rechallenge in 3 patients.73–75 A case that was de-
scribed by Lerche et al76 was excluded as amylase was not ele-
vated more than 3 ULN.
Tamoxifen
A total of 8 case reports, fulfilling inclusion criteria, had
implicated tamoxifen as the cause of AP, one of which had pos-
itive rechallenge test after few days.77 Severe pancreatitis was
reported in the 2 patients,77,78 where death was the outcome
of one of them.78 Hypertriglyceridemia was the main mechanism
of DIAP37 and is likely related to increases in liver secretion of
VLDL secondary to tamoxifen agonistic activity on estrogen re-
ceptor in addition to decreased activity of lipoprotein lipase and
hepatic triglyceride lipase.79 Another 3 case reports were excluded
as the case reports failed to fulfill our criteria for diagnosis of AP.
Telaprevir and Tetracycline
Both telaprevir80 and tetracycline81 have case report each of
mild DIAP with favorable outcome and with positive rechallenge
after excluding other common etiologies.
Trimethoprim/Sulfamethoxazole
A total of 8 case reports have linked trimethoprim/
sulfamethoxazole with DIAP.82–89 Two case reports described
positive rechallenge,83,89 and death was the outcome in other 2
cases.85,87 One of the case reports described positive lymphocyte
stimulation test with sulfamethoxazole, which may state that sul-
famethoxazole is the main derivative of the reported DIAP.88
Class Ib
A total of 26 medications had at least 1 case report with pos-
itive rechallenge, but these case reports failed to document exclu-
sion of other causes or other possible etiologies were available.
These drugs are azathioprine, bortezomib, carbamazepine, cloni-
dine, clozapine, cytosine arabinoside, dapsone, dexamethasone,
fenofibrate, hydrocortisone, 6-mercaptopurine (6-MP), methimazole,
mirtazapine, nelfinavir, nitrofurantoin, omeprazole, paclitaxel, pent-
amidine, prednisone, propofol, quetiapine, sodium stibogluconate,
sorafenib, tigecycline, valproic acid, and valsartan. See Supplemental
Digital Content 3, http://links.lww.com/MPA/A747, for a complete
list of case references.
Azathioprine
A total of 11 cases in 8 case reports had implicated azathio-
prine in DIAP. Three case reports described positive rechallenge,
but all of them failed to mention exclusion of other causes
of AP.90–92
Bortezomib
Drug-induced acute pancreatitis was described in patients re-
ceiving treatment for multiple myeloma with bortezomib. Talamo
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Drug-Induced Acute Pancreatitis
et al,93 Gupta et al,94 and Solakoglu et al95 described cases with
positive rechallenge, but dexamethasone, a class Ib medication,
was given with bortezomib in all patients. A case described by
Elouni et al96 was excluded because of absence of characteristic
pain, and lipase was elevated but <3 ULN.
Carbamazepine
Laczek et al97 described DIAP in a patient who was taking
200 mg carbamazepine 3 times a day of for trigeminal and
glossopharyngeal neuralgia, with positive rechallenge after 2 days,
but the patient was using alcohol daily. A case described Soman
and Swenson98 was excluded, as amylase and lipase were not
more than 3 ULN.
Clonidine
Amery et al99 described 3 cases of DIAP with clonidine used
for hypertension treatment, with positive rechallenge in 1 patient,
but patient was concomitantly taking a thiazide, and gallstones
were present in abdominal ultrasound.
Clozapine
Chengappa et al100 described a case of DIAP in a patient,
26 days after taking clozapine daily for schizophrenia with posi-
tive rechallenge after about the same duration, but abdominal ul-
trasound showed presence of gallstones.
Cytosine Arabinoside
Cytosine arabinoside (cytarabine) was described to cause
DIAP during treatment of acute myeloblastic leukemia101 and
acute lymphoblastic leukemia.102,103 In 2 cases, positive rechal-
lenge was described, but in 1 case, other medications known to
cause DIAP were present,101 and in the other cases, exclusion of
other causes was not mentioned.103 A case series by McGrail
et al104 was excluded because of absence of exact details on char-
acters of pain and which patients had positive CT findings.
Dapsone
Jha et al105 described mild DIAP in a patient taking dapsone
for dermatitis herpetiform with positive rechallenge, but the pa-
tient was also taking cimetidine (class 1A).
Dexamethasone
Two case reports described mild DIAP with favorable out-
come,106,107 with positive rechallenge in 1 case report, but other med-
ications known to cause DIAP were present in the case report.107
Fenofibrate
Kassim et al108 described a DIAP in a patient 2 days after tak-
ing 160 mg fenofibrate daily for dyslipidemia with positive re-
challenge after 2 days also, but imaging showed evidence of
pancreatic head mass, and the patient was taking atorvastatin
(class III) in addition to fenofibrate.
Hydrocortisone
Khanna and Kumar109 described DIAP in a patient, after
2 days of taking dexamethasone with positive rechallenge, but ex-
clusion of other causes was not mentioned. Another case of severe
DIAP was described by Nelp110 in treatment of asthma, which
ended with death of the patient.
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Simons-Linares et al
6-Mercaptopurine
Bank and Wright111 described a case report of DIAP with
6-MP, with positive rechallenge, but the patient was taking predni-
sone (class II) and 5-aminosalicylate derivative (class Ia).
Methimazole
Five case reports implicated methimazole in DIAP favorable
outcome in all cases. Agito and Manni112 described a case with
positive rechallenge, but endoscopic retrograde cholangiopancre-
atography was done before the first attack of pancreatitis.
Mirtazapine
Multiple cases reported described DIAP, with positive re-
challenge in 1 patient, but the patient also was consuming 8 to
16 units of alcohol weekly.113 Chen et al114 reported a case of
moderate AP in a patient with hypertriglyceridemia as a possible
mechanism of DIAP.37
Nelfinavir, Nitrofurantoin, and Omeprazole
Nelfinavir,115 nitrofurantoin,116 and omeprazole117 have 1
case report each, with positive rechallenge, but other medications
were present in nelfinavir and omeprazole, while exclusion of other
causes was not mentioned in the case implicating nitrofurantoin.
Paclitaxel
Positive rechallenge was described in 1 patient, but the pa-
tient was receiving dexamethasone (class Ib) as part of the chemo-
therapy.118 A case described by Hoff et al119 was excluded from
final analysis, as amylase and lipase were not elevated more than
3 ULN, and no confirmatory imaging was available.
Pentamidine
Multiple case reports had implicated pentamidine in all of its
forms, intravenous, intramuscular, and aerosolized. Three patients
in 2 case reports had positive rechallenge, but no details were available
on exclusion of other causes.120,121 Case reports described by O'Neil
et al122, in addition to Murphey and Josephs,121 were excluded from
final analysis as they failed to fulfill required pancreatitis diagnosis.
Prednisone
A total of 8 cases in 5 case reports were described in literature,
with positive rechallenge in 1 case described by Nelp,110 but the
patient had evidence of gallstones on abdominal ultrasound.123–126
Propofol
Propofol was implicated in 10 cases, with positive rechallenge
in 1 patient described by Kumar et al.127 In this case, hypertriglyc-
eridemia was the likely mechanism of AP, but gallstones were also
evident in the abdominal ultrasound.
Quetiapine
Gropper and Jackson,128 in addition to Chang et al,129 de-
scribed 2 case reports with positive rechallenge, but both patients
were taking valproic acid (class Ib) before the AP attack. A total of
5 case reports had hypertriglyceridemia as the possible mecha-
nism of DIAP.37
Sodium Stibogluconate
Four case reports described DIAP in patients receiving so-
dium stibogluconate for treatment of leishmaniasis, with positive
rechallenge in 1 case, but the patient was also receiving cyclospor-
ine (class III), and hypercalcemia was present in the case.130
1268 www.pancreasjournal.com
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 48, Number 10, November/December 2019
Sorafenib
Li and Srinivas131 described a case with positive rechallenge
in a patient receiving sorafenib for renal cell carcinoma, but the
patient was also taking other medications, including simvastatin
(class Ia) and mirtazapine (class 1b) before the AP attack.
Tigecycline
Hemphill and Jones132 described a case of DIAP in a patient
receiving tigecycline for treatment of acute bronchitis in a patient
with cystic fibrosis with positive rechallenge, but the fact that the
patient has cystic fibrosis, a known cause of AP, downgraded the
medication to class Ib. One of the case reports described by
Davido et al133 and another one described by Marshall134 were ex-
cluded because of absence of required elements for AP diagnosis.
Valproic Acid
A total of 18 cases in 13 case reports described DIAP in patients
receiving valproic acid, with positive rechallenge in 1 patient, but other
medications known to cause DIAP were present in the same case.135
Valsartan
Can et al136 described AP in a 58-year-old male receiving
valsartan for hypertension with positive rechallenge in 6 weeks,
but during workup of other causes of AP, gallstones were evident
on abdominal ultrasound, which is a known cause of AP.
Class II
A total of 17 medications had at least 4 cases in the literature
with consistent latency. These drugs are all-trans retinoic acid,
L-asparaginase/peg-asparaginase, canagliflozin, chlorothiazide,
codeine, dideoxy inosine (didanosine), gold therapy, hydrochloro-
thiazide, interferon α2b/ribavirin, lisinopril, liraglutide, meglumine
antimonate, nilotinib, olanzapine, prednisolone, riluzole, and
sitagliptin. See Supplemental Digital Content 3, http://links.
lww.com/MPA/A747, for a complete list of case references.
Class III
A total of 30 medications had at least 2 cases in the literature
with no consistent latency among cases and no rechallenge. These
medications included aspirin, atorvastatin, capecitabine, captopril,
ceftrixone, celecoxib, chlorthalidone, ciprofloxacin, clarithromycin,
cocaine, cyclosporine, doxycycline, erythromycin, everolimus,
exenatide, indomethacin, interferon α2b, irbesartan, ketorolac, met-
formin, metolazone, minocycline, naproxen, orlistat, pazopanib,
phenformin, ritonavir, saw palmetto, tacrolimus, and vildagliptin.
See Supplemental Digital Content 3, http://links.lww.com/MPA/
A747, for a complete list of case references.
Class IV
Class IV drugs included drugs not fitting into the earlier de-
scribed classes, single case report published in medical literature,
without rechallenge. A total of 78 medications were described in this
group, including L-arginine, adefovir, ado-trastuzumab emtansine,
albiglutide, allopurinol, amitriptyline, amoxicillin/clavulanate,
ampicillin, anagrelide hydrochloride, artesunate, atenolol, axitinib,
benazepril, bendroflumethiazide, bezafibrate, boceprevir, brentuximab
vendontin, calcium carbonate, Ceramium kondoi, danazol, diclofenac,
dideoxycytidine, dimethyl fumarate, entecavir, ergotamine tartrate,
estramustine phosphate, ethacrynic acid, ezetimibe, famciclovir, flu-
conazole, fluvastatin, gadobenate dimeglumine (MULTIHANCE),
glimepiride, horsetail infusions (Equisetum arvense), ibuprofen,
icodextrin, ifosfamide, imatinib, interferon α2a, interferon β1a,
interleukin 2, ketoprofen, lacosamide, lamivudine, lamotrigine,
© 2019 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 48, Number 10, November/December 2019
lanreotide autogel, levetircetam, mefenamic acid, micafungin,
miltefosine, montelukast, motesanib, mycophenolate mofetil,
naltrexone, nifuroxazide, nivolumab, octreotide, oxacalcitriol,
oxyphenbutazone, paromomycin, phenolphthalein, ramipril, ris-
peridone, roxithromycin, secnidazole, sertraline, stavudine,
sunitinib, tacalcitol, telmisartan, theophylline, tinidazole,
tocilizumab, vedolizumab, vemurafenib, venlafaxine, vinblastine
and ziprasidone. See Supplemental Digital Content 3, http://links.
lww.com/MPA/A747, for a complete list of case references.
Cases reporting combination of medications make it difficult to de-
termine the exact causative drugs. These combinations included
mifepristone/gemeprost/acetaminophen-codeine, lovastatin/gemfibrozil,
infliximab/adalimumab, diphenoxylate/atropine, dabigatran/lamotrigine
and ezetimibe/simvastatin. Combination chemotherapy was also
reported as a possible cause of AP. These combinations include
docetaxel/carboplatin, lobaplatin/etoposide, vinblastine/cisplatin,
and vincristine/doxorubicin/cyclophosphamide/ifosfamide/asparaginase.
See Supplemental Digital Content 3, http://links.lww.com/MPA/
A747, for a complete list of case references.
Classification of Medications by Severity
Table 3 summarizes medications by severity of DIAP re-
ported. Mild pancreatitis–only category included medications that
had only mild DIAP reported in the literature. Moderate severity
category included medications that had at least 1 case with moder-
ately severe DIAP with no severe DIAP. Severe category included
medications that had at least 1 case report with severe DIAP. Se-
verity of AP was based on the Revised Atlanta Classification.2
Mortality Cases
Of the 577 cases, 59 cases (10%) ended in patient death for
different reasons, implicating a total of 34 medications. Supplemental
Digital Content 1, Supplemental Table 2, http://links.lww.com/MPA/
A745, provides details on the mortality cases, regarding amylase/
lipase levels, type of pancreatitis, time to death (from time of pan-
creatitis diagnosis to death), and cause of death, if mentioned.
DISCUSSION
The incidence of AP continues to rise, and 20% to 30% of
cases are labeled as idiopathic in etiology. It is important to estab-
lish the etiology of AP to decrease morbidity and mortality related
to an AP episode, especially in patients with recurrent AP. Al-
though more than 180 drugs have been implicated to cause AP,
the vast majority probably do not. Drug-induced acute pancreatitis
is a rare condition and represents a diagnostic challenge to the cli-
nician; this is because our current DIAP knowledge is very limited
as the vast majority of the evidence is from case reports. In an ef-
fort to improve the current literature, we conducted a systematic
review, focusing on DIAP cases that met the widely accepted diag-
nosis criteria according to the Revised Atlanta Classification.
There have been several DIAP critical reviews published, but
none has addressed the issue of DIAP mortality, accurate AP
diagnosis, and AP severity; hence, we performed our system-
atic review focusing on accurately reported diagnosis criteria
and severity as per the Revised Atlanta Classification. We excluded
78 cases that did not fit the diagnosis criteria. In addition, despite
efforts of improving AP outcomes over the years, as well as the
careful selection of drugs for patients to avoid undesired adverse
events such as DIAP, the reported implicated drugs have increased
from 120 drugs in 2007 to 183 drugs in 2018. Badalov et al2,3 pub-
lished a classification system for DIAP based on the level of evi-
dence in published case reports, and our study applied this system
to weigh the reported cases included in our systematic review. Inter-
estingly, there were 24 drugs (20%) classified as class Ia (original
© 2019 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Drug-Induced Acute Pancreatitis
Badalov et al2,3 classification) in 2007 compared with 32 drugs
(17.4%) in 2018. In addition, for class Ib, there were 18 (15%) ver-
sus 26 drugs (14.2%); class II, 10 (8.3%) versus 17 drugs (9.2%);
class III, 25 (20.8%) versus 30 drugs (16.3%); and class IV, 43
(35.8%) versus 78 drugs (42.6%), in the year 2007 compared with
2018, respectively. We observed a decrease in the proportion of
DIAP-implicated drugs classified as class Ia (strongest evidence)
and an increase in class IV drugs (weakest evidence).
The mean age in our study was 46.8 years (range, 17–92 years),
271 were female (47%), 109 (59.7%) drugs caused mild AP,
19 (10.3%) caused moderately severe AP, and 55 (30%) drugs caused
severe AP (Table 3). Ninety-nine patients (17.2%) had pancreatic ne-
crosis, and death was the outcome in 59 patients (10.2%). Our system-
atic review is unique because we report outcomes of AP severity,
including pancreatic necrosis as well as mortality data. The rate of
pancreatic necrosis and mortality found in our study is consistent with
the reported for AP cases in the literature (Supplemental Digital Con-
tent 1, Supplemental Table 2, http://links.lww.com/MPA/A745).
Interestingly, there were 25 drugs that caused very high triglyc-
eride levels, which was thought to be the mechanism of the DIAP in
76 cases.32 The later cases of hypertriglyceridemia-associated DIAP are
described and discussed in detail in a separate systematic review.32 It is
important to mention that hypertriglyceridemia-associated DIAP seems
to be a different entity, and its exact mechanism or pathways for pancre-
atic injury are still unknown. There are at least 3 hypotheses: (1) the
drug causing hypertriglyceridemia, and then as a secondary process
the hypertriglyceridemia induces AP (which may not fall under
the category of DIAP); (2) the drug injures the pancreas through a
direct toxic effect, and the hypertriglyceridemia worsens the process
or acts as enhancer for the pancreatic injury and inflammation; (3)
the drug injures the pancreas through a direct toxic effect, and the
hypertriglyceridemia does not have any effects on the AP inflam-
mation process. See Supplement Digital Content 4, http://links.
lww.com/MPA/A748, for a complete list of cases that are thought
to cause DIAP through a hypertriglyceridemia mechanism.
While most of the drugs thought to be the cause of DIAP
have been published in the form of case reports, only 2 drugs have
solid evidence from retrospective cohorts and randomized trials
(azathioprine and didanosine), and the true magnitude of DIAP
is still unknown. The current review studied the accuracy of the di-
agnosis of AP and also classified the severity of the cases as per
the Revised Atlanta Classification.
Most of the proposed DIAP mechanisms of injury have not
been proven yet, but the mechanistic behind is probably due to
an idiosyncratic reaction (hypersensitivity or toxic metabolite ac-
cumulation) rather than an intrinsic toxicity. Interestingly, there
is some in vitro and clinical evidence of these mechanisms.3 Large
population-based studies exist for azathioprine and 6-MP, as well
as data from multiple randomized controlled trials that have re-
ported these medications' adverse effects, including DIAP from
these drugs in patients with inflammatory bowel disease,137–140 al-
though one can argue that patients with inflammatory bowel dis-
ease have other influencing factors and risk factors for AP
(gallstones, polypharmacy, dysregulated immunity). In the case
of sulfasalazine, a study showed in vitro positive lymphocyte stim-
ulation test to sulfasalazine in AP.141 In the case of codeine, a hy-
perconstriction of the sphincter of Oddi is a proposed mechanism.
Other proposed mechanism includes angiotensin-converting
enzyme inhibitors causing pancreatic ductal edema through
the kallikrein-kinin pathway. Most recently, our group reported
in a systematic review that more than 25 drugs have been de-
scribed to cause hypertriglyceridemia-associated DIAP, which
seems to have a very different natural history of the disease
compared with the classic hypertriglyceridemia AP (not caused
by a drug).37
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Simons-Linares et al Pancreas • Volume 48, Number 10, November/December 2019

TABLE 3. Classification of Medications by AP Severity

Mild Only Moderate Severe

Ado-traztuzumab Emtansine Losartan Adefovir Acetaminophen
Albiglutide Mefenamic acid Artesunate Allopurinol
All-trans retinoid acid 6-Mercaptopurine Bortezomib Androgenic anabolic steroids
5-Amino salicylate α-Methyldopa Cannabis Azathioprine
Amiodarone Metolazone Ceftriaxone Calcium carbonate
Amitriptyline Micafungin sodium Clozapine Canagliflozin
Amoxicillin/clavulanate Minocycline Doxycycline Capecitabine
Ampicillin Montelukast Imatinib Celecoxib
Anagrelide hydrochloride Motesanib In vitro fertilization Chlorothiazide
L-Arginine Nadolol Interferon α2b Chlorthalidone
Aspirin Naltrexone Interferon β1a Cimetidine
Atenolol Naproxen Methimazole Clonidine
Atorvastatin Nifuroxazide Metronidazole Cocaine
Axitinib Nitrofurantoin Nilotinib Cyclosporine
Benazepril Nivolumab Octreotide Cytosine arabinoside
Bendroflumethiazide Orlistat Riluzole Dapsone
Bezafibrate Oxacalcitriol Ritonavir Dideoxy inosine (didanosine)
Boceprevir Oxyphenbutazone Sorafenib Dideoxycytidine
Brentuximab vendontin Paromomycin Tacalcitol Enalapril
Captopril Pazopanib Ergotamine tartrate
Carbamazepine Perindopril Estrogen and related products
Carbimazole Phenolphthalein Ethacrynic acid
C. kondoi Pravastatin Famciclovir
Clomiphene Procainamide Furosemide
Codeine Pyritinol Hydrochlorothiazide
Danazol Ramipril Hydrocortisone
Dexamethasone Ranitidine Indomethacin
Diclofenac Risperidone Interferon α2b/ribavirin
Dimethyl fumarate Rosuvastatin lacosamide
Entecavir Roxithromycin L-Asparaginase/peg-asparaginase
Erythromycin Saw Palmetto Liraglutide
Estramustine phosphate Saxagliptin Lisinopril
Everolimus Secnidazole Meglumine antimonate
Exenatide Sertraline Metformin
Ezetimibe Stavudine Miltefosine
Fenofibrate Sulindac Mycophenolate mofetil
Fluconazole Sunitinib Nelfinavir
Fluvastatin Telaprevir Olanzapine
Gadobenate dimeglumine (Multihance) Telmisartan Omeprazole
Glimepiride Tetracycline Paclitaxel
Gold therapy Theophylline Pentamidine
Horsetail infusions (E. arvense) Tigecycline Phenformin
Ibuprofen Tinidazole Prednisolone
Icodextrin Tocilizumab Prednisone
Ifosfamide Valsartan Propofol
Interferon α2a Vedolizumab Quetiapine
Interleukin 2 Vemurafenib Simvastatin
Irbesartan Vinblastine Sitagliptin
Isoniazid Ziprasidone Sodium stibogluconate
Ketoprofen Tacrolimus
Ketorolac Tamoxifen
Lamivudine Trimethoprim/sulfamethoxazole
Lamotrigine Valproic acid
Lanreotide autogel Venlafaxine
Levetiracetam Vildagliptin

1270 www.pancreasjournal.com © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Pancreas • Volume 48, Number 10, November/December 2019
CONCLUSIONS
Drug-induced AP exists but is rare. Most data come from
case reports, which are a low quality of evidence. In our article,
we summarize the data from reported cases of DIAP according
to the Revised Atlanta Classification and excluded cases that did
not meet these classification diagnosis criteria. We have also sum-
marized the cases that developed necrotizing pancreatitis and also
the mortality cases data, which is important and new compared
with other published DIAP review articles. We conclude that pan-
creatic necrosis and mortality rates are similar to the reported rates
in AP not caused by a drug. Finally, we have also summarized the
severity of AP according to the Revised Atlanta Classification and
summarized the drugs that cause mild, moderately severe, and se-
vere DIAP, concluding that most drugs cause mild DIAP. The cli-
nician should be aware that certain drugs have more robust
evidence than others to associate the drug to DIAP, and unfortu-
nately, only 2 drugs are well described in the literature to explain
causation rather than association (azathioprine and didanosine).
Larger case-control studies on DIAP to study the true potential
of the implicated drugs described in this review are needed. To
conclude, a formal standardized DIAP reporting system is also es-
sential for future research in this topic.
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