Table 1

Characteristics of the 59 included studies

Study	Country	Study design*	Drug of interest	Paediatric study?	Stated or apparent study objective
Studies reporting only DIP detection methods (n=7)
Samuels et al 11	USA	Primary study	L-asparaginase	Yes	Not reported
Bale et al 12	USA	Primary study	Valproic acid	No	To assess the usefulness of serum amylase screening in patients taking VPA
Torelli et al 13	Italy	Primary study	Valproic acid	No	Serum amylase values in children about to be treated or already treated with sodium valproate were examined as an indicative parameter and eventual sign of pancreatic disease
Nguyen et al 15	USA	Primary study	L-asparaginase	Yes	To assess the relative diagnostic value of serial pancreatic sonograms in children receiving asparaginase
Castiglione et al 18	Italy	Primary study	Azathioprine	No	To monitor for the development of preclinical DIP during AZA therapy in Crohn's patients
Raja et al 22	Denmark	Primary study	PEG-asparaginase	Yes	To examine whether asparaginase-induced AP develops slowly over time or rather develops suddenly in children
Raja et al 23	Denmark	Primary study	PEG-asparaginase	Yes	To explore if hypertriglyceridaemia or early elevations in pancreatic enzymes were associated with the development of AP

Studies reporting both DIP detection methods and diagnostic processes (n=7)
Wyllie et al 14	USA	Primary study	Valproic acid	No	To review all reports of pancreatitis associated with valproic acid in the literature and to describe four cases the authors saw between 1981–1983
Maxson et al 16	USA	Primary study	Didanosine	No	To better define the relationship between 2',3'-Dideoxyinosine for AIDS and acute pancreatitis by reporting on the incidence and natural history of pancreatitis and pancreatic enzyme elevations
Chambon et al 17	France	Primary study	PEG-asparaginase	No	To report acute necrotic pancreatitis secondary to asparaginase in two patients
Laugel et al 19	France	Primary study	PEG-asparaginase	Yes	To clarify the clinical course, the diagnostic signs, risk factors and therapeutic options for children with asparaginase-induced AP
Dhir et al 20	USA	Narrative review	None	No	To discuss the clinical and epidemiological features of DIP, commonly associated drugs and conditions, possible pathogenic mechanisms and a systematic approach to diagnosis and management of DIP
Balani and Grendell6	USA	Narrative review	None	No	To review the epidemiology, diagnosis, management and prevention of DIP
Anonymous21	Not reported	Narrative review	None	No	A review on prevention and management of drug-induced pancreatitis by identifying the offending agent and understanding the underlying mechanism

Studies reporting only DIP diagnostic processes (n=45)
Mallory and Kern68	USA	Narrative review	None	No	To critically review the English language literature pertaining to drug-induced pancreatitis and attempt to determine whether the reported association between each drug and pancreatitis was valid
Steinberg24	USA	Narrative review	None	No	To explore the mechanisms and management of acute drug and toxin pancreatitis
Haber et al 25	USA	Primary study	6-mercaptopurine	No	To characterise the frequency, severity and reversibility of DIP associated with 6-mercaptopurine in the treatment of inflammatory bowel disease
Scarpelli26	USA	Narrative review	None	No	To explore the toxicology of the pancreas
Delcenserie et al 27	France	Narrative review	None	No	To discuss standardised criteria of causality for a diagnosis of drug-induced pancreatitis
Lankisch et al 28	Germany	Primary study	None	No	To determine the incidence and severity of DIP in German centres of gastroenterology
McArthur29	USA	Narrative review	None	No	Not stated
Fernandez et al 30	Spain	Primary study	Mesalamine	No	To report two cases of pancreatitis associated with mesalamine
Maringhini et al 31	Italy	Primary study	Enalapril	No	To describe three cases of pancreatitis associated with enalapril
Chetaille et al 32	France	Primary study	Minocycline	No	To report the first two cases of AP associated with minocycline, a third-generation tetracycline used in the treatment of acne
Berthelemy and Pariente33	France	Narrative review	None	No	Not stated
Eland et al 34	The Netherlands	Primary study	None	No	To assess which drugs were associated with AP in Dutch adverse drug reaction reports
Alvarez and Zimmerman35	USA	Narrative review	PEG-asparaginase	Yes	To report the incidence of pancreatitis in patients treated with PEG-asparaginase
Delcenserie36	France	Clinical practice guideline	None	No	Discussion of the criteria for causality assessment for DIP
Grauso-Eby et al 37	USA	Primary study	Valproic acid	Yes	To report four cases of VPA-induced AP and review the literature for cases
Chaudhari et al 38	USA	Primary study	IFN-alpha-2b and RBV combination	No	To determine the incidence, clinical presentation, and outcome of acute pancreatitis in a large cohort of HCV-infected patients treated with IFN-alpha and RBV combination therapy
Trivedi and Pitchumoni67	USA	Narrative review	None	No	To update the information on DIP (case report review) and offer simple guidelines using a new classiﬁcation of drugs associated with DIP
Werlin and Fish39	USA	Primary study	Valproic acid	Yes	To characterise valproic acid-associated pancreatitis in children
Kemppainen and Puolakkainen40	Finland	Narrative review	None	No	Focuses on the search for other aetiological factors of AP once alcohol and gallstones have been excluded
Mennecier et al 41	France	Primary study	None	No	To determine the incidence of non-alcoholic non-biliary pancreatitis and identify causes, comparing severity by aetiology
Nguyen-Tang et al 42	Switzerland	Narrative review	None	No	None specifically reported, although it is clearly a narrative review of DIP
Weersma et al 43	The Netherlands	Primary study	AZA	No	To evaluate the prevalence of pancreatic autoantibodies in patients with azathioprine-induced pancreatitis in Crohn’s disease and in controls with Crohn’s disease, hypothesising that most or all patients with azathioprine-induced pancreatitis have circulating pancreatic autoantibodies
Ando et al 44	Japan	Primary study	IFN-alpha	No	To describe AP associated with PEG-IFN plus RBV treatment in three patients
Thomae et al 45	Germany	Primary study	None	No	To investigate which drugs are associated with the occurrence of acute hepatitis and acute pancreatitis (idiopathic or drug-induced; non-alcoholic)
Ahmad and Mahmud46	UK	Primary study	Orlistat	No	To report two patients who developed acute pancreatitis with elevated pancreatic enzymes following orlistat therapy
Butt et al 47	USA	Primary study	Oxaliplatin	No	To report a case series of patient with AP presumably caused by oxaliplatin
Nitsche et al 48	UK	Narrative review	None	No	Not stated
Vinklerová et al 49	Czech Republic	Primary study	None	No	To determine the incidence, aetiology and severity of drug-induced pancreatitis during a 2 year period in a tertiary hospital. (they actually included only cases of AP in their sample and determined the proportion presumed to have DIP, not the incidence of DIP among all hospital admissions)
Bai et al 50	The Netherlands	Primary study	None	Yes	To identify common comorbidities and concomitant pancreatitis aetiologies in children with DIP. Secondarily, to identify the most commonly associated drugs in the different age groups, evaluate management practices and compare drug-associated cases with non-drug-associated cases
Barreto et al 51	USA	Primary study	None	No	To determine the incidence, presentation, clinical course and outcome of DIP among patients admitted to a public hospital in Australia (they actually only included patients with AP in their sample and determined the proportion that were presumed to have DIP, not the incidence of DIP among all admissions to the hospital)
Spanier et al 52	Australia	Primary study	None	No	To evaluate the prevalence of pancreatitis-associated drugs in a Dutch cohort of patients admitted for AP and to identify the proportion of AP possibly attributable to the use of drugs
Marot et al 53	Belgium	Primary study	Tigecylcine	No	To report two new cases of tigecycline-induced mild AP and to review the literature
Meftah et al 54	Morocco	Primary study	None	No	To present four cases of DIP
Minen et al 55	Italy	Primary study	None	Yes	(1) to assess the aetiological factors of acute and recurrent pancreatitis in a paediatric population from a tertiary care hospital; (2) to assess the usefulness of imaging studies in diagnosing aetiologies of pancreatitis
Ledder et al 56	Australia/New Zealand	Primary study	AZA	Yes	To report on four paediatric cases of inflammatory bowel disease in which a second thiopurine was introduced successfully after an initial thiopurine was suspected to have caused pancreatitis
Morimoto et al 57	Japan	Primary study	Asparaginase	Yes	A presentation of two paediatric ALL cases of asparaginase-associated pancreatitis diagnosed at an early stage based on elevated serum elastase-1 levels, in the presence of normal serum amylase levels
Yanar et al 58	Turkey	Primary study	None	No	To report two patients with suspected DIP
Heap et al 59	UK/USA	Primary study	Thiopurine therapy	No	To (a) characterise the clinical features of thiopurine-induced pancreatitis and (b) identify clinical useful genetic markers that might predict development of this serious adverse drug reaction
Ruellan et al 60	France	Primary study	Morphine sulfate	No	To report AP after morphine sulfate ingestion in young patients
Sunga et al 61	Korea	Primary study	Ciprofloxacin	No	To identify the clinical features and natural course of drug-induced pancreatitis by ciprofloxacin during therapeutic use
Tenner62	USA	Narrative review	None	No	To explain that drug induced acute pancreatitis does occur, but it is rare, and over diagnosis leads to misconceptions about the disease resulting in inappropriate patient care, increased litigation and a failure to address the true entity: idiopathic acute pancreatitis
Cofini et al 63	Italy	Primary study	Valproic acid	Yes	To describe their experience regarding clinical presentation, diagnosis, management and outcome in children with VPA-induced AP
Jones et al 64	USA	Narrative review	None	No	To critically review the epidemiology, pathogenesis, diagnosis and presentation of drug-induced pancreatitis, as well as discuss drugs and classes of drugs strongly implicated in mediating or modulating AP based on well-documented case reports and lab investigation
Nesvaderani et al 65	Australia	Primary study	None	No	To determine whether alcohol was the main cause of pancreatitis in Western Sydney through retrospective case analysis, and to determine the epidemiology, aetiology and outcomes of acute pancreatitis
Yamada et al 66	Japan	Primary study	Nilotinib	No	To report two cases of nilotinib-induced pancreatitis

*Primary studies included clinical trials, prospective and retrospective cohort studies and case series.
ALL, acute lymphocytic leukaemia; AP, acute pancreatitis; AZA, azathioprine; DIP, drug-induced pancreatitis; IFN, interferon; PEG, pegylated; RBV, ribavarin; VPA, valproic acid.