Drug-Induced Acute Pancreatitis: An Evidence-Based Review

Transcription

1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2007;5: REVIEW Drug-Induced Acute Pancreatitis: An Evidence-Based Review NISON BADALOV,* ROBIN BARADARIAN, KADIRAWEL ISWARA, JIANJUN LI, WILLIAM STEINBERG, AND SCOTT TENNER *Division of Gastroenterology, Maimonides Medical Center; State University of New York, Mount Sinai School of Medicine, Brooklyn, New York, The George Washington University School of Medicine, Washington, DC See CME exam on page 644. The diagnosis of drug-induced acute pancreatitis often is difficult to establish. Although some medications have been shown to cause acute pancreatitis with a large body of evidence, including rechallenge, some medications have been attributed as a cause of acute pancreatitis merely by a single published case report in which the investigators found no other cause. In addition, some medications reported to have caused acute pancreatitis have obvious patterns of presentation, including the time from initiation to the development of disease (latency). There also appear to be patterns in the severity of disease. After reviewing the literature, we have classified drugs that have been reported to cause acute pancreatitis based on the published weight of evidence for each agent and the pattern of clinical presentation. Based on our analysis of the level of evidence, 4 classes of drugs could be identified. Class I drugs include medications in which at least 1 case report described a recurrence of acute pancreatitis with a rechallenge with the drug. Class II drugs include drugs in which there is a consistent latency in 75% or more of the reported cases. Class III drugs include drugs that had 2 or more case reports published, but neither a rechallenge nor a consistent latency period. Class IV drugs were similar to class III drugs, but only 1 case report had been published. Our analysis allows an evidence-based approach when suspecting a drug as causing acute pancreatitis. Drug-induced acute pancreatitis is a rare entity that often is challenging for clinicians. 1 4 Although more than 100 drugs have been implicated in causing acute pancreatitis, many case reports suffer from a combination of inadequate criteria for the diagnosis of acute pancreatitis, failure to rule out more common causes, and/or a lack of a rechallenge with the medication. Drug-induced pancreatitis rarely is accompanied by clinical or laboratory evidence of a drug reaction, such as rash, lymphadenopathy, and/or eosinophilia. Although a positive rechallenge with a drug is the best evidence available for cause and effect, it is not proof. It is clear that many patients with idiopathic pancreatitis or microlithiasis have recurrent attacks of acute pancreatitis. Therefore, stopping and restarting a drug with recurrence of pancreatitis may be a coincidence and not cause and effect. Despite the lack of a rechallenge, a drug may be strongly suspected if there is a consistent latency among the case reports between initiating the drug and the onset of acute pancreatitis. In this review, we attempt to classify drugs that have been reported to cause pancreatitis based on the weight of evidence for each agent and pattern in presentation. Methods Identification and Classification of Drugs A MEDLINE search ( ) of the English language literature for all cases with acute pancreatitis revealed 1214 case reports that allowed classification of 120 drugs. Search terms included pancreatitis and drug-induced or medication-induced, drug, and medication. The search was confined to human studies. Relevant bibliographies were included. The latest search date was July 1, Pharmaceutical and Food and Drug Administration data were not used for this analysis. All published case reports were reviewed by 2 physicians who performed independent literature searches. These 2 physicians reviewed the published reports for classification based on the inclusion criteria described later. Cases were included in the analysis if the following criteria were met. First, only cases published in the scientific/medical literature were included initially for review. Although isolated abstracts were not included, letters to the editor that provided the required information were included. Second, reports needed to provide the name, latency, and the dose of the medication attributed as causing acute pancreatitis. Third, the diagnosis of acute pancreatitis must have been established by clinical symptoms, increase of the amylase and/or lipase level greater than 3 times the upper limit of normal, and/or computerized tomography (CT) or ultrasonography findings consistent with acute pancreatitis. The cases were studied for the level of evidence of acute pancreatitis. Cases were considered definite if imaging, CT, ultrasonography, laparotomy, or autopsy confirmed the presence of acute pancreatitis. Cases were considered probable if the typical symptoms were present with a greater than 3-fold increase of serum amylase and/or lipase level. Cases in which the diagnosis of acute pancreatitis was less clear, such as pain in the absence of increases in amylase level or asymptomatic increases Abbreviations used in this paper: CT, computerized tomography; Cyt, cytosine; 6-MP, 6-mercaptopurine by the AGA Institute /07/$32.00 doi: /j.cgh

2 June 2007 DRUG INDUCED ACUTE PANCREATITIS 649 Table 1. Classification System of Drug-Induced Acute Pancreatitis Class Ia drugs At least 1 case report with positive rechallenge, excluding all other causes, such as alcohol, hypertriglyceridemia, gallstones, and other drugs Class Ib drugs At least 1 case report with positive rechallenge; however, other causes, such as alcohol, hypertriglyceridemia, gallstones, and other drugs were not ruled out Class II drugs At least 4 cases in the literature Consistent latency ( 75% of cases) Class III drugs At least 2 cases in the literature No consistent latency among cases No rechallenge Class IV drugs Drugs not fitting into the earlier-described classes, single case report published in medical literature, without rechallenge of the amylase level were considered possible and not included in the final analysis. The cases for a particular drug were reviewed as a group for the latency, the time interval between starting the drug and the onset of acute pancreatitis. Cases were characterized further into mild acute pancreatitis or severe acute pancreatitis. Severe pancreatitis was defined as death, sepsis, necrosis, abscess, symptomatic pseudocyst, or organ failure. As a group, the individual drugs were studied to determine if there was evidence of a recurrence of acute pancreatitis with a rechallenge with the medication. Cases were reviewed to determine the possible causes of pancreatitis, such as alcoholism, gallstones, hypertriglyceridemia, or other medications. The cases were evaluated for a description of a rechallenge causing a recurrence of pancreatitis. We also sought to determine if there were different latencies (the interval between starting a drug and the induction of pancreatitis) and whether the latencies could be categorized. Results Based on our analysis of the level of evidence, 4 classes of drugs could be identified (Table 1). Class I drugs includes medications in which at least 1 case report described a recurrence of acute pancreatitis with a rechallenge with the drug. Class I drugs were subdivided further into class Ia and class Ib. Class Ia drugs are the drugs in which all potential causes of acute pancreatitis such as gallstones, hypertriglyceridemia, alcohol, hypercalcemia, and other medications were ruled out as a cause of acute pancreatitis. Class Ib drugs are drugs in which reports describe a recurrence of pancreatitis with the re-introduction of the drug, however, potential causes of acute pancreatitis were not ruled out or obviously present (eg, in this category, although the case report may show a rechallenge if the patient was taking other medications known to cause acute pancreatitis, or known to have gallstones, or use alcohol, the case report would be included in class 1 with a subtype b). Class II drugs include drugs in which there is a consistent latency in 75% or more of the reported cases. At least 4 case reports were required to be included in this category. Our analysis further found that 3 distinct drug latencies could be discerned: short (latency of 24 hours), intermediate (latency of 1 30 days), and long (latency 30 days). Class III drugs include drugs that had neither a rechallenge nor a consistent latency period. At least 2 cases were required to be included in this class. Class IV drugs were similar to class III drugs, but only 1 case report was available. Class I Drugs Forty-three drugs met the criteria to be included in class I (Supplementary Table 1, see supplementary material on-line at at The medications in which there was a rechallenge and other causes of acute pancreatitis had been ruled out (class Ia) are as follows: mesalamine dipentum (azodisalicylate), bezafibrate, cannabis, carbimazole, codeine, enalapril, isoniazide, metronidazole, pravastatin, premarin, procainamide, pyritinol, simvastatin, stibogluconate, sulfamethoxazole, sulindac, tetracycline, and valproic acid. Class Ib drugs have at least 1 published case showing a rechallenge, but the case failed to rule out other common causes of acute pancreatitis. Class Ib drugs include the following: all-trans-retinoic acid, -methyldopa, amiodarone, mesalamine, azathioprine, clomiphene, cytosine arabinoside, dapsone, dexamethasone, ethinylestradiol/lynesterol, furosemide, hydrocortisone, ifosfamide, lamivudine, losartan, lynesterol/methoxyethinnylestradiol, 6-mercaptopurine (6-MP), meglumine, methimazole, nelfinavir, norethindronate/mestranol, omeprazole, pentamidine, sulfamethazole, and trimethoprim-sulfamethoxazole. -Methyldopa: Class Ib -methyldopa is used commonly in the management of hypertension in pregnant patients. Four cases have implicated this drug as causing acute pancreatitis, with a latency period of less than 2 weeks in each case (range, 1 14 days). 5,63,64 All 4 reported cases had mild outcome. All-Trans-Retinoic Acid: Class Ib Four cases implementing all-trans-retinoic acid as a cause of drug-induced acute pancreatitis have been reported. 6,65 67 All cases were mild, and the dose of all trans-retinoic acid used was up to 100 mg/day. Latencies were intermediate in 3 cases (2 3 wk) and long (20 wk) 66 in 1 of the cases. All 4 cases were confounded by the use of drug(s) already implicated as a cause of acute pancreatitis (methylprednisone, 6-MP, and cytosine arabinoside). Mesalamine: Class Ia Several mesalamine preparations have been implicated in causing acute pancreatitis, including disodium azodisalicylate (Dipentum; Pfizer Inc, Morris Plains, NJ), 8 both oral (Asacol; Proctor & Gamble, Cincinnati, OH) 9,10,68,69 and enema (Rowasa; Proctor & Gamble) forms of mesalamines, 70 and sulfasalazine (Azulfidine; Pfizer). 71,72 Mesalamine and disodium azodisalicylate have case reports showing rechallenges. The latencies from drug exposure to development of acute pancreatitis were 3 months, 1 year, and 2 years, which is atypical for mesalamine preparations. 73 One case occurred only a few hours after initial ingestion. 74 In addition, several case reports have been published in the literature describing the development of acute pancreatitis in a pediatric population taking oral and rectal mesalamine Amiodarone: Class Ib Three cases of amiodarone-induced acute pancreatitis have been reported. 7,78,79 Bosch and Bernadich 7 described a case

3 650 BADALOV ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 6 of acute pancreatitis in a patient receiving 800 mg of amiodarone for 4 days. After resolution of symptoms and normalization of amylase and lipase levels the patient was given a rechallenge with 100 mg/day of amiodarone, leading to a recurrence of acute pancreatitis. Famularo et al 79 described a patient who developed acute pancreatitis while taking 600 mg of amiodarone daily. The dose of amiodarone was reduced to 200 mg/day; however, the patient did not have a recurrence of pancreatitis. The investigators suggested a dose-related rather than idiosyncratic reaction to amiodarone. Azathioprine and 6-Mercaptopurine: Class Ib Azathioprine and its metabolite, 6-MP, have strong evidence implicating them as agents that cause acute pancreatitis ,38 In the National Cooperative Crohn s Disease study, almost 6% of 116 patients treated with 6-MP developed acute pancreatitis. 80 During a 15-year period from 1969 to 1985, Haber et al 81 treated 400 patients with inflammatory bowel disease with 6-MP. Thirteen (3.25%) developed acute pancreatitis thought to be related to the medication. There are 20 case reports of acute pancreatitis resulting from therapy with azathioprine and 6-MP ,38,80 87 Four definite cases (confirmed by CT and ultrasonography) had a positive rechallenge, 3 with azathioprine and 1 with 6-MP. 38 Bezafibrate: Class Ia Bezafibrate is used to treat dyslipidemia. Known side effects include dermatitis, hepatitis, rhabdomyolysis, and coagulation disturbances. Only 1 case report of bezafibrate-induced severe acute pancreatitis (200 mg/day) has been published. 14 The patient developed acute pancreatitis on 3 separate occasions after exposure to the drug. Cannabis: Class Ia Cannabis is the most popular illicit drug in the world. Grant and Gandhi 15 described a single case of recurrent severe acute pancreatitis after heavy cannabis smoking. The patient started smoking increased amounts of cannabis for 3 months before presentation and subsequently had recurrent attacks of acute pancreatitis while using cannabis in the hospital. There are no reported cases with oral cannabinoids. Carbimazole: Class Ia Carbimazole is a 3-carbmethoxy methimazole derivative used commonly outside the United States in the treatment of Graves disease. Marazuela et al 16 reported a case of a 33-yearold woman with Graves disease receiving 45 mg of carbimazole daily. Thirty days after the initiation of treatment, the patient developed acute pancreatitis, associated with erythema nodosum and intrahepatic cholestasis. Codeine: Class Ia There have been 5 cases of codeine-induced acute pancreatitis reported in the literature. 18 Hastier et al 18 described a series of 4 case reports with latencies of minutes. Interestingly, all 4 patients had undergone cholecystectomy in the past, and had taken 40 mg of codeine, except for 1 patient (60 mg). Three of 4 cases described earlier had positive rechallenges with consistent latencies of minutes, and 3 of 4 cases had mild clinical outcome. Cytosine Arabinoside: Class Ib Cytosine arabinoside is a chemotherapeutic agent that has been shown to cause acute pancreatitis with a rechallenge ,88 Altman et al 19 described a patient who, after 2 successive 5-day courses of cytosine arabinoside (160 mg/day), developed acute pancreatitis. This occurred during the middle of his third cycle. Months later, on the fourth day of receiving another course of cytosine arabinoside, the patient again developed acute pancreatitis. Dapsone: Class Ib Dapsone is a nonsulfonamide antibiotic with activity similar to that of sulfonamides. There have been 2 cases of dapsone-induced acute pancreatitis. Jha et al 22 described a patient who developed acute pancreatitis 4 weeks after initiating treatment with dapsone 100 mg/day and cimetidine 400 mg twice a day for the treatment of dermatitis herpetiformis and dyspepsia, respectively. Four months later on re-introduction of dapsone alone, the patient developed acute pancreatitis within 3 weeks. Corp and Ghishan 89 described a second case of dapsone-induced pancreatitis as a part of sulfone syndrome, a hypersensitivity reaction to dapsone (which includes fever, rash, hemolytic anemia, acute hepatic injury, and atypical lymphocytosis). Dexamethasone (Class Ib) and Other Steroids There is 1 case report in the literature of dexamethasone-induced acute pancreatitis with a positive rechallenge. 23 This patient had multiple medical problems and had other risks factors for developing acute pancreatitis, including alcohol abuse. The patient s onset of clinical and laboratory features of acute pancreatitis began 2 days after administration of highdose dexamethasone (4 mg every 6 hours). Symptoms recurred within 5 days of rechallenge. In addition, Khanna et al 28 reported a case of hydrocortisone (Class Ib) induced acute pancreatitis with a positive rechallenge. The patient developed acute pancreatitis on the second day of treatment. Other steroids have been implicated as causing acute pancreatitis, including prednisone, prednisolone, cortisone acetate, and adrenocorticotropic hormone More than half of the patients died of acute pancreatitis, suggesting severe disease. However, these case reports fail to clearly exclude other potential confounding factors and there is no consistent latency to implicate these drugs. Enalapril: Class Ia There have been 7 well-documented case reports of enalapril-induced acute pancreatitis. 24,25,36,100,101 Two of the 7 cases were confirmed with rechallenge. 24,25 The dose ranged from 2.5 to 20 mg/day, with the majority of patients taking 20 mg of enalapril daily. Latencies ranged from 5 days to 1 year. Two of the cases had a severe outcome. 24,101 There are several case reports implicating other ACE inhibitors as a cause of acute pancreatitis, two with Captopril (Class III) (102,103), six with Lisinopril (Class III) ( ) (latencies ranging from 3 hours to 5 years), one with Benazepril (Class IV) (110), and one with Ramipril (Class IV) (111). Estrogens: Class Ib There have been 40 case reports that have documented the association between estrogen use and the development of

4 June 2007 DRUG INDUCED ACUTE PANCREATITIS 651 acute pancreatitis. 26,43,47, The mechanism of action probably is secondary to the hypertryglyceridemic effects of estrogens because most cases described have been associated with serum triglyceride levels greater than 1000 mg/dl. Familial hyperlipoproteinemia also has been found in these patients. 116,117 However, Blake and Pitcher 47 described a patient who developed acute pancreatitis after being on Premarin, (Wyeth Pharmaceuticals Inc, Madison, NJ) (class Ia) 6.25 mg/ day (conjugated estrogen) for 2 years. Subsequently, the patient developed 2 bouts of acute pancreatitis on rechallenge with Premarin. Interestingly, unlike most cases of estrogen-induced acute pancreatitis, there was no associated hypertriglyceridemia in this case. The latencies of the cases published have varied from 2 months to 4 years after initiation of the drug. Furosemide: Class Ib There are 5 cases of furosemide-induced pancreatitis that have been reported in the literature. 27,119,120 Only 1 of these cases was confirmed with a rechallenge. 27 The patient had received 40 mg/day of furosemide. After 5 weeks of continuous therapy, the patient developed acute pancreatitis. When rechallenged, acute pancreatitis occurred within 24 hours. The latencies in other cases were shorter (1 day, 3 days, and 2 weeks). All cases have had a mild outcome. Ifosfamide: Class Ib Ifosfamide-induced acute pancreatitis has been reported. 29,121 In the 2 published reports, acute pancreatitis occurred within 48 hours of exposure to the drug. In the case reported by Izraeli et al, 29 multiple attacks of acute pancreatitis developed after rechallenges with different doses of ifosfamide. The attacks occurred within 1 4 days after rechallenge. Interestingly, the higher the dose, the more rapid the recurrence of acute pancreatitis. This suggests a dose-response (pancreatitis) relationship. Isoniazid: Class Ia Eight cases of isoniazid-induced acute pancreatitis have been reported in the literature , All of the patients were taking 300 mg/day, except for 1 of the patients who was taking 200 mg/day. 33 Four of these cases were confirmed with rechallenge. The onset of acute pancreatitis after the initiation of isoniazid ranged from 6 hours to 21 days. The onset of acute pancreatitis with a rechallenge occurred in the first 6 hours in 2 of the patients 30,31 ; and at 5 days 32 and 21 days 33 in the other reported cases. All cases were mild. Six of 8 patients were men, ages years. Interestingly, 3 of the cases occurred in patients with renal insufficiency. Lamivudine: Class Ib There is only 1 case report of lamivudine-induced acute pancreatitis. 34 The patient was using digoxin and furosemide on an irregular basis for 10 years before presentation. He had a history of chronic hepatitis B complicated by cirrhosis with ascites. Three days after beginning lamivudine, a clinically significant increase in the serum amylase level developed, which led to discontinuation of lamivudine. After normalization of amylase levels, he was rechallenged with lamivudine alone. This resulted in symptomatic acute pancreatitis with high amylase levels. The diagnosis was confirmed by CT. Complications included multisystem organ failure, which eventually led to death. The investigators did not comment whether other common causes were ruled out (gallstones, hypertriglyceridemia, and so forth). Losartan: Class Ib Two cases of losartan-induced acute pancreatitis have been reported. 35,36 Both patients received enalapril before exposure to losartan 50 mg/day. In the case reported by Bosch, 35 enalapril (10 mg/day for 5 months) was discontinued secondary to the development of a chronic cough. In the case reported by Birck et al, 36 the patient developed acute pancreatitis, which led to the discontinuation of enalapril (2.5 mg for 5 days) and losartan. After normalization of amylase and lipase levels, both patients were rechallenged with losartan alone. This resulted in a recurrence of acute pancreatitis. In the case reported by Bosch, 35 the latency and repeat latency were 3 days each. In the case reported by Birck et al, 36 the latency and repeat latency were 7 days and 2 days, respectively. The outcome was mild. Meglumine (Class Ib)/Stibogluconate (Class Ia) Meglumine and stibogluconate are antimonial drugs used in the treatment of visceral leishmaniasis. Five cases of meglumine-associated acute pancreatitis have been reported in the literature. 37, Only 1 of these cases was confirmed with a rechallenge. 37 Stibogluconate has been implicated as causing acute pancreatitis in 22 cases, with latencies ranging from 2 to 22 days. 53, Overall, doses have varied from 600 to 2000 mg/day. In 1 of these case reports, a well-described rechallenge was reported. 53 Many of the cases of acute pancreatitis caused by stibogluconate have been severe, 129,130 and 2 cases resulted in death. 131,132 Methimazole: Class Ib There is only 1 case report of methimazole-induced acute pancreatitis. 39 Three weeks after taking the drug, the patient had acute pancreatitis and painful parotid swelling. Because there was no case report of methimazole-induced pancreatitis/parotitis, the patient was rechallenged with the drug (30 mg/day). The patient developed acute pancreatitis/parotitis within 24 hours. Possible causes were excluded; however, the investigator did not report triglyceride levels. The patient s clinical course was uncomplicated and mild. Metronidazole: Class Ia Acute pancreatitis, defined by discharge data, has been estimated to occur in 4.6 of 10,000 persons receiving metronidazole. 134 Seven case reports of metronidazole-induced acute pancreatitis have been reported, 40,41, with 2 of 7 cases having well-described rechallenges. 40,41 One case clearly excluded other causes of acute pancreatitis, including alcohol and gallstones. Acute pancreatitis developed after the first 2 doses and was mild in outcome. 41 Nelfinavir: Class Ib Di Martino et al 42 described a single patient who presented with severe acute pancreatitis after receiving 2 months of nelfinavir (2250 mg/day), didanosine (300 mg/day), nevirapine (400 mg/day), and lamivudine (300 mg/day). Before this combination of antiretroviral therapy, the patient was receiving lamivudine (300 mg/day), ritonavir (800 mg/day), stavudine (80 mg/day), and saquinavir (800 mg/day) for a duration of 17 months. The outcome of the case was mild.

5 652 BADALOV ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 6 Omeprazole: Class Ib Youssef et al 44 reported a single case of omeprazoleinduced pancreatitis. Acute pancreatitis developed after 2 months of therapy with omeprazole 20 mg/day. In addition to omerprazole, the patient was taking lisinopril and hydrocholorothiazide, drugs implicated as causing acute pancreatitis. On rechallenge, the patient had a recurrence of acute pancreatitis. The outcome was severe, including respiratory failure and pseudocyst formation. Of note, Eland et al 140 did not find an increase in the risk of acute pancreatitis and the use of acidsuppressive therapy in a study of more than 180,000 human subjects. Pentamidine: Class Ib There have been 16 case reports of pentamidine-associated acute pancreatitis, 45, with 2 cases confirmed by a rechallenge. 45 Pentamidine-induced acute pancreatitis has been reported with both parenteral and aerosolized 45,150,151 forms. There has been a very consistent latency period between the administration of the drug and the occurrence of pancreatitis, and in the vast majority of cases the latency period has been between 1 and 3 weeks. Of notice, parenteral pentamidineassociated pancreatitis has a particularly severe outcome. Twenty-five percent of the cases in the literature have been severe, with approximately 10% resulting in death. Pravastatin and Other Statins: Class Ia There has been 1 case of pravastatin-induced acute pancreatitis reported. 46 The patient developed acute pancreatitis after taking pravastatin (20 mg/day) for 6 months. The patient re-introduced pravastatin (40 mg/day), which resulted in the recurrence of mild pancreatitis within 7 days. Other common causes of acute pancreatitis were ruled out. There have been 3 case reports of simvastatin-induced (class Ia) acute pancreatitis. 50,152,153 Only 1 of the 3 cases was confirmed with a rechallenge. 50 A case of atorvastatin 40 mg/day salicylate 100 mg/day, 154 atorvastatin and lisinopril, 109 and a case of lovastatin (20 mg twice a day) gemfibrozil (300 mg twice a day) induced pancreatitis have been reported 155 ; neither of the cases had rechallenges. Singh et al, 156 described a patient who developed acute pancreatitis while taking atorvastatin (Class III). When switched to rosuvastatin (Class IV), recurrent disease developed. This suggests a class effect for statin drugs. A single case report of Fluvastatin (Class IV) 57 induced acute pancreatitis has also been described in the literature, with latency of 3 months, and mild outcome. Procainamide: Class Ia There is only 1 case report of procainamide-induced acute pancreatitis. 48 The patient had a greater than 3-fold increase in the serum amylase level and abdominal pain 7 months after starting this drug (1.5 mg/kg/day). Three to 4 weeks after restarting the drug, the patient suffered a second attack of acute pancreatitis. The patient s course was uncomplicated and mild. Pyritinol: Class Ia A single case report of pyritinol-induced acute pancreatitis has been reported by Straumann et al. 49 The patient developed acute pancreatitis after taking pyritinol (600 mg/day) for 3 months. On subsequent exposures, the patient developed acute pancreatitis within 6 days, 4 days, and 2 hours. The investigators suggested an immune-mediated cause for the development of acute pancreatitis. Sulfa Drugs: Class Ia The sulfonamides have been grouped together frequently because of the similarities in their chemical structure. Case reports of sulfamethazole-induced (class Ib) 51 and sulfamethoxazole-induced (class Ia) 52 acute pancreatitis with positive rechallenges have been reported in the literature. The latencies of these 2 drugs were 4 days and 10 weeks, respectively. Rechallenge with the medication resulted in acute pancreatitis within 1 day in both cases. Trimethoprim-sulfamethoxazole (class Ib) also has caused acute pancreatitis in 1 case with rechallenge. 59 The patient developed mild pancreatitis after 7 days of receiving 960/4800 mg/day of trimethoprim-sulfamethoxazole. Acute pancreatitis recurred within 72 hours after rechallenge. Although we have listed trimethoprim-sulfamethoxazole together with the sulfa drugs, it is not known whether it is the sulfa or nonsulfa moiety of this drug that is responsible for acute pancreatitis Sulindac: Class Ia There have been 4 cases of sulindac-associated acute pancreatitis. The latencies range from 3 weeks to 5.5 years, with 3 of 4 cases occurring within 1 4 months. All 4 cases had positive rechallenge 54 56,163,164 ; however, the case described by Lilly 163 did not meet our criteria for the diagnosis of acute pancreatitis on rechallenge. Patients were taking mg of sulindac daily. Rechallenges resulted in a recurrence of symptoms 1 2 months after restarting the medication. Tetracycline: Class Ia There are many case reports dating back to the 1950s and 1960s implicating intravenous tetracycline as a cause of fatal hepatitis and pancreatitis in pregnant women. At autopsy, several of these patients were found to have fatty liver of pregnancy and hemorrhagic pancreatitis. 57,58, However, the role of tetracycline is not clear. Kunelis et al 168 reported that 6 of 8 patients with fatty liver of pregnancy given tetracycline intravenously had acute pancreatitis at autopsy, whereas 4 of 4 patients with fatty liver of pregnancy who were not given tetracycline also had this finding at post mortem. To our knowledge, there is no case report of intravenous tetracycline causing acute pancreatitis in the absence of fatty liver of pregnancy. More recently, 5 cases of oral tetracycline have suggested a causal relationship to acute pancreatitis, with latencies of 1 6 weeks in 4 of 5 cases. 57,58,167 All but 1 case occurred within 1 8 weeks of initiating treatment, with doses ranging from 1 to 2 g/day. The latencies of the 2 cases 57,58 with rechallenge varied from 7 days to 3 months. Valproic Acid: Class Ia Three cases of valproic acid induced acute pancreatitis with rechallenges have been reported in the literature Two of these cases occurred in children taking between 15 and 45 mg/kg/day, with latencies of 3 6 months. Similarly, the rechallenge latencies were consistent, from 1.5 to 3 months. In addition to these cases, another 30 cases have been reported without rechallenges Three quarters of these cases occurred in the pediatric population. Almost half of the reported cases of val-

6 June 2007 DRUG INDUCED ACUTE PANCREATITIS 653 Acetominophen Codeine Erythromycin Propofol Alphamethyldopa 5-ASA Alltransretinoic acid Azathioprine/5-MP Clozapine L-Asparaginase Meglumine Pentamidine Stibogluconate Dideoxyinosine Estrogens Tamoxifen Chlorthiazide Valproate -Case reports with rechallenge -Case report with no rechallenge Days Figure 1. Drugs with a consistent latency (time between drug and onset of acute pancreatitis) in more than 75% of the cases ( 4 case reports). Three patterns of consistent latency were noted: short latency of less than 24 hours, an intermediate latency of greater than 24 hours and less than 30 days, and a long latency of greater than 30 days., case reports with rechallenge; K, case reports with no rechallenge. proate-induced acute pancreatitis have been severe, with associated complications such as necrosis, 62 pseudocyst, 176,177,184,185 and death. 178,179,186 Class II Drugs The drugs listed in the class II category include cases in which a consistent latency has been reported in more than 75% of the cases, and at least 4 case reports were found in the literature (Figure 1). Three patterns of consistent latency were noted: short latency of less than 24 hours (1 day), an intermediate latency of greater than 1 day and less than 30 days, and a long latency of greater than 30 days. The following medications have met the criteria to be included in class II: acetaminophen, methyldopa, 5,63,64 mesalamine, 8,9,10,68,69 all-transretinoic acid, 6,65 67 azathioprine/6-mp, 11 13,38,80 87 codeine, 18,87 chlorthiazide, clozapine, =3=-dideoxyinosine, erythromycin, estrogens, 26,43,47, L-asparginase/pegaspargase, meglumine, 37, pentamidine, 45, propofol stibogluconate, 53, tamoxifen, and valproate , Some of the class I drugs in addition to having rechallenges have consistent latencies and are included as class II drugs and in Figure 1. These drugs are thought to have the most convincing evidence in causing acute pancreatitis. Reports of class I medications that had rechallenges are depicted as boxes, whereas all other cases are depicted as circles. Class III Drugs The data implicating the drugs in class III are weaker than for the previous 2 classes. Only 2 published case reports giving the dosage and latency are required to be in this category. The case reports here lack any rechallenge as well as any consistent latency. These cases include alendronate, 237 captopril, 102,103 carbamazepine, ceftriaxone, 241,242 cimetidine, 243,244 clarithromycin, 245,246 chlorthalidone, 194,247 cyclosporine, 248,249 gold, 250,251 hydrocholorothiazide, indomethacin, 256,257 interferon and interferon/ribavirin, isotretinoin, ketorolac, 267,268 lisinopril, metalazone, 269,270 metformin, mirtazepine, 274,275 naproxen, 276,277 and paclitaxel Class IV Drugs Many single case reports exist in the literatures that describe the association of various medications with the development of acute pancreatitis. These drugs have the weakest association to pancreatitis. Some of the cases are not clearly written, do not describe rechallenges, and the cases do not have a pattern of latency. Drugs included in this class are brief reports with limited information and are as follows: ampicillin, 281 bendroflumethiazide, 282 benzapril, 110 bethamethasone/ roxithromycin, 283 capecitabine, 284 colchicines, 285 cyproheptadine, 286 danazol, 287 diazoxide, 288 diclofenac, 289 ergotamine, 290 ethacrinic acid, 291 famcyclovir, 292 finasteride, 293 fluvastatin, 157

7 654 BADALOV ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 6 ketoprofen, 294 lovastatin, 155 mefanamic acid, 295 nitrofurantoin, 296 octreotide, 297,298 oxyphenbutazone, 299 penicillin, 300 phenolphthalein, 301 propoxyphene, 302 ramipril, 111 ranitidine, 303 rifampin, 304 risperidone, 305 ritonovir, 306 sertraline, 307 strychnine, 308 tacrolimus, 309 and vigabatrin/lamotrigine. 310 In addition, there have been several case reports implicating the combination of medications used in chemotherapeutic regimens. Combination vincristine, 5-fluorouracil, cisplatin, interleukin-2, cyclophosphamide, and doxorubicin have been implicated as causing acute pancreatitis These cases are difficult to interpret. The investigators did not rule out more common causes of acute pancreatitis such as alcohol and gallstones, and appear to preferentially have attributed the pancreatitis to a particular medication despite being given in combination with other medications. Also, 2 cases of vinorelbineinduced acute pancreatitis have been reported. 317,318 Neither of the 2 cases had a 3-fold increase of amylase/lipase levels or had CT/ultrasonography findings consistent with acute pancreatitis. Discussion Although uncommon, defining a drug as causing acute pancreatitis poses a challenge to clinicians. To provide an evidencebased review of the literature, we chose to analyze this area by studying the patterns of drug-induced injury in published case reports. These reports allow the critical analysis of published information provided by the physician investigators and the editors of the journal. We did not use data from pharmaceutical or Food and Drug Administration reports because, in general, these sources do not have sufficient detail as to causation. Case reports, if detailed properly, can give more definitive information as to the diagnosis of pancreatitis and whether other causes besides drugs have been properly ruled out. The cause of drug-induced pancreatic injury is unknown. By using the classification of Zimmerman 319 originally described for drug hepatotoxicity, drugs associated with tissue-specific injury can be divided into those with intrinsic toxicity for the organ involved and those that cause injury as a result of host idiosyncrasy. Intrinsic toxins are those that cause damage in a dose-dependent fashion, irrespective of the host response. The injury is reproducible at certain doses, usually in human and animal models, and often has a short and relatively consistent latency. There is very little evidence that intrinsic toxicity of a drug is a cause of pancreatitis in human beings. Only 3 drugs, acetaminophen (4 cases), erythromycin (3 cases), and carbamazepine (2 cases), have been associated with acute pancreatitis in the setting of an overdose ,213,214,239 Considering the number of cases of acetaminophen overdose and the rarity of pancreatitis in this setting, it is much more likely that idiosyncratic reaction is playing a role rather than intrinsic drug toxicity. Erythromycin, as noted before, is a known prokinetic agent that stimulates motilin release, and large doses may cause acute pancreatitis by causing spasm of the sphincter of Oddi, leading to abrupt pancreatic-duct hypertension and pancreatitis. As opposed to intrinsic toxicity, idiosyncratic reaction appears to be the mechanism of drug injury in the vast majority of cases. Idiosyncratic reactions are unpredictable, not dose dependent, and have a low incidence in human beings. These cannot be reproduced easily in animal models, and the latency period could be short, intermediate, or long. Idiosyncratic reactions can be divided further into those secondary to hypersensitivity reactions and those caused by the accumulation of a toxic metabolite or some intermediary injurious substance. Hypersensitivity reactions are caused by an immunologic response of the host in response to the drug and tend to occur with a latency of 1 6 weeks after exposure. Classically, hypersensitivity reactions are accompanied by a rash, fever, joint pains, lymphadenopathy, and eosinophilia. When the host is re-exposed to the agent that caused hypersensitivity, the drug reaction is reproduced with a shorter latency than the original attack. There are little experimental data confirming an immunologic basis to drug-induced pancreatitis disease. One such study by Chiba et al 320 showed an in vitro positive lymphocyte-stimulation test to sulfasalazine in a patient who previously had acute pancreatitis, which was thought to be secondary to this drug. Ben-Ami et al 251 reported a case with a positive lymphocyte-stimulation test with parenteral gold in a patient with acute pancreatitis. It is quite unusual for drug-induced pancreatitis to be accompanied by the classic systemic symptoms and signs of hypersensitivity. Nevertheless, most drugs that are implicated in causing acute pancreatitis follow the pattern of hypersensitivity in that the latency between initiating the drug and the onset of pancreatitis is 1 6 weeks and rechallenge with the drug leads to prompt pancreatitis within 1 3 days. Examples of these drugs are azathioprine/6-mp, captopril, the sulfa antibiotics, 5-aminosalicylates, oral tetracycline, and metronidazole. Idiosyncratic reactions that might be related to the accumulation of a toxic metabolite or some other intermediary are identified by a longer latency period of several months to possibly years before pancreatitis is produced. Furthermore, rechallenge with the offending drug causes pancreatitis in months, rather than the short latency seen in hypersensitivity reactions. Examples of drugs that fit into this category of a toxic metabolite or toxic intermediary include valproic acid, 2=3=dideoxyinosine, estrogens, isotretinoin, and possibly thiazides. Only in the case of estrogens, tamoxifen, and isotretinoin has a possible/probable intermediary been found (ie, hypertriglyceridemia). In the other cases, such an intermediary has not been found. Last, codeine likely causes a constriction of the sphincter of Oddi, particularly in patients susceptible to developing acute pancreatitis. Although drug-induced hepatotoxicity appears to occur more commonly in women, this does not appear to be true in drug-induced acute pancreatitis (male to female ratio, 1:1.3; Table 1). The mean age of the patients affected with this disorder is 48 years, however, the range is large (8 87 y). In addition, most cases of drug-induced acute pancreatitis appear to be mild, with the exception of famciclovir, indomethacin, lamivudine, nelfinavir, omeprazole, ritonavir, sertraline, tacrolimus, and vigabatin/lamotrigine (Supplementary Table 2). Conclusions We have classified 120 drugs that have been implicated in the scientific literature as causing pancreatitis (Table 2). The drugs are categorized based on the weight of evidence favoring this association. Two pieces of evidence link certain drugs to acute pancreatitis; recurrence of pancreatitis with rechallenge (class I drug) and a consistent latency between ingestion of the drug and the development of pancreatitis (class II drug). The evidence linking the remainder of the drugs to pancreatitis is weaker, but these associations cannot be excluded. Future publications describing drug-induced pancreatitis should include the following. First, acute pancreatitis must be defined by clinical, laboratory, and imaging criteria to establish the diagnosis. Second, other causes of acute pancreatitis need to be

8 June 2007 DRUG INDUCED ACUTE PANCREATITIS 655 Table 2. Summary of Drug-Induced Acute Pancreatitis Based on Drug Class Class Ia Class Ib Class II Class III Class IV -methyldopa All-trans-retinoic acid Acetaminophen Aledronate Adrenocorticotrophic Octreotide Azodisalicylate Bezafibrate Cannabis Carbimazole Codeine Cytosine Arabinoside Dapsone Enalapril Furosemide Isoniazid Mesalamine Metronidazole Pentamidine Pravastatin Procainamide Pyritonol Simvastatin Stibogluconate Sulfamethoxazole Sulindac Tetracycline Valproic acid Amiodarone Azathioprine Clomiphene Dexamethasone Ifosfamide Lamivudine Losartan Lynesterol/methoxyethinylestradiol 6- MP Meglumine Methimazole Nelfinavir Norethindronate/mestranol Omeprazole Premarin Sulfamethazole Trimethoprimsulfamethazole Chlorthiazide Clozapine DDI Erythromycin Estrogen L-asparaginase Pegasparagase Propofol Tamoxifen Atorvostatin Carbamazepine Captopril Ceftriaxone Chlorothalidone Cimetidine Clarithromycin Cyclosporin Gold Hydrochlorothiazide Indomethacin Interferon/ribavirin Irbesartan Isotretinoin Ketorolac Lisinopril Metalozone Metformin Minocycline Mirtazapine Naproxen Paclitaxel Prednisone Prednisolone hormone Ampicillin Bendroflumethiazide Benzapril Betamethazone Capecytabine Cisplatin Colchicine Cyclophosphamide Cyproheptidine Danazol Diazoxide Diclofenac Difenoxylate Doxorubicin Ethacrinic acid Famciclovir Finasteride 5-fluorouracil Fluvastatin Gemfibrozil Interleukin-2 Ketoprofen Lovastatin Mefanamic acid Nitrofurantoin Oxyphenbutazone Penicillin Phenophthalein Propoxyphene Ramipril Ranitidine Rifampin Risperidone Ritonovir Roxithromycin Rosuvostatin Sertaline Strychnine Tacrolimus Vigabatin/lamotrigine Vincristine clearly ruled out, including gallstones, alcohol, hypertriglyceridemia, anatomic anomalies including pancreas divism, and tumors. Third, the medication being assigned as the contributory cause of acute pancreatitis must be described in terms of the dose, duration/latency, and the existence of rechallenge. Further research may lead to the discovery of underlying mechanisms in which drugs cause acute pancreatitis , , Supplementary Data Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at References 1. Lankisch PG, Droge M, Gottesleben F. Drug induced acute pancreatitis: incidence and severity. Gut 1995;37: Eland IA, van Puijenbroek EP, Sturkenboom MJCM, et al. Drug associated acute pancreatitis: twenty-one years of spontaneous reporting in the Netherlands. Am J Gastroenterol 1999;94: Trivedi CD, Pitchumoni CS. Drug-induced pancreatitis: an update. J Clin Gastroenterol 2005;39: Mallory A, Kern F Jr. Drug-induced pancreatitis: a critical review. Gastroenterology 1980;78: Van der Heide H, Haaft MA. Methyldopa induced pancreatitis. BMJ 1981;282: Teng HW, Bai LY, Chao TC, et al. Acute pancreatitis during all-trans-retinoic acid treatment for acute promyelocytic leukemia in a patient without overt hypertriglyceridemia. Jpn J Clin Oncol 2005;35: Bosch X, Bernadich O. Acute pancreatitis during treatment with amiodarone. Lancet 1997;350: Poldermans D, van Blankenstein M. Pancreatitis induced by disodium azodisalicylate. Am J Gastroenterol 1998;83: Sachedina B, Saibil F, Choen LB, et al. Acute pancreatitis due to 5-aminosalicylate. Ann Intern Med 1989;110: Toubanakis C, Batziou E, Galanopoulos G, et al. Acute pancreatitis after long term therapy with mesalazine, and hyperamylasemia associated with azathioprine in a patient with ulcerative colitis. Eur J Gastroenterol Hepatol 2003;15: Guillaume P, Grandjean E, Male RJ. Azathioprine associated acute pancreatitis in the course of chronic active hepatitis. Dig Dis Sci 1984;29: Paloyan D, Levin B, Simonowitz D. Azathioprine associated acute pancreatitis. Dig Dis 1977;22: Nogueira JR, Freedman MA. Acute pancreatitis as a complication of imuran therapy in regional enteritis. Gastroenterology 1972;82: Gang N, Langevitz P, Livneh A. Relapsing acute pancreatitis induced by re-exposure to the cholesterol lowering agent bezafibrate. Am J Gastroenterol 1999;94: Grant P, Gandhi P. A case of cannabis-induced pancreatitis. JOP 2004;5: Available at: Marazuela M, Sanchez de Paco G, Jiminez I, et al. Acute pancreatitis, hepatic cholestasis, and erythema nodosum induced by carbimazole for treatment of Graves disease. Endocr J 2002;49: Castro MR, Nguyen TT, O Brien T. Clomiphene-induced severe hypertriglyceridemia and pancreatitis. Mayo Clin Proc 1999;74: Hastier P, Buckley MJM, Peten EP, et al. A new source of drug-induced acute pancreatitis: codeine. Am J Gastroenterol 2000;95: Altman AJ, Dinndorf P, Quinn JJ. Acute pancreatitis in association with cytosine arabinoside therapy. Cancer 1982;49: McBride CE, Yavorski RT, Moses FM, et al. Acute pancreatitis

9 656 BADALOV ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 6 associated with continuous infusion cytarabine therapy: case report. Cancer 1996;77: McGrail LH, Sehn LH, Weiss RB, et al. Pancreatitis during therapy of acute myeloid leukemia: cytarabine related? Ann Oncol 1999;10: Jha SH, Reddy JA, Dave JK. Dapsone-induced acute pancreatitis. Ann Pharmacother 2003;37: Levine PA, McGuire RF. Corticosteroid induced pancreatitis: a case report demonstrating recurrence with rechallenge. Am J Gastroenterol 1988;83: Maringhini A, Termini A, Patti R, et al. Enalapril-associated acute pancreatitis: recurrence after rechallenge. Am J Gastroenterol 1997;92: Carnovale A, Esposito P, Bassano P, et al. Enalapril-induced acute recurrent pancreatitis. Dig Liver Dis 2003;35: Banks S, Marks IN. Hyperlipemic pancreatitis and the pill. Postgrad Med J 1960;46: Jones PE, Oelbaum MH. Furosemide induced pancreatitis. BMJ 1975;1: Khanna S, Kumar A. Acute pancreatitis due to hydrocortisone in a patient with ulcerative colitis. J Gastroenterol Hepatol 2003; 18: Izraeli S, Adamson PC, Blaney SM, et al. Acute pancreatitis after ifosfamide therapy. Cancer 1994;74: Rabassa AA, Trey G, Shukla U, et al. Isoniazid induced acute pancreatitis. Ann Intern Med 1994;121: Stephenson I, Wiselka MJ, Qualie MJ. Acute pancreatitis induced by isoniazid in the treatment of tuberculosis. Am J Gastroenterol 2001;96: Chan KL, Chan HS, Lui SF, et al. Recurrent acute pancreatitis induced by isoniazid. Tuber Lung Dis 1994;75: Chow KM, Szeto CC, Leung CB, et al. Recurrent acute pancreatitis after isoniazid. Neth J Med 2004;62: Soylu AR, Dokmeci G, Tezel A, et al. Lamivudine-induced acute pancreatitis in a patient with decompensated HBV-related chronic liver disease. J Clin Gastroentorol 2004;38: Bosch X. Losartan-induced acute pancreatitis. Ann Intern Med 1997;127: Birck R, Keim V, Fiedler F, et al. Pancreatitis after losartan. Lancet 1998;351: de Lalla F, Pellizzer G, Gradoni L, et al. Acute pancreatitis associated with the administration of meglumine antimoniate for the treatment of visceral leishmaniasis. Clin Infect Dis 1993; 16: Cappell MS, Das KM. Rapid development of pancreatitis following reuse of 6-mercaptopurine. J Clin Gastroenterol 1989;11: Taguchi M, Yokota M, Koyano H, et al. Acute pancreatitis and parotitis induced by methimazole in a patient with Graves disease. Clin Endocrinol 1999;51: Sanford KA, Mayle JE, Dean HA, et al. Metronidazole associated pancreatitis. Ann Intern Med 1998;109: Celifarco A, Warschauer C, Burakoff R. Metronidazole induced pancreatitis. Am J Gastroenterol 1989;84: Di Martino V, Ezenfis J, Benhamou Y, et al. Severe acute pancreatitis related to the use of nelfinavir in HIV infection: report of a case with positive rechallenge. AIDS 1999;13: Davidoff F, Tishler S, Rosoff C. Marked hyperlipidemia and pancreatitis associated with oral contraceptive therapy. N Engl J Med 1973;289: Youssef SS, Iskandar SB, Scruggs J, et al. Acute pancreatitis associated with omeprazole. Int J Clin Pharmacol Ther 2005; 43: Murphy RL, Noskin GA, Ehrenpreis ED. Acute pancreatitis associated with aerosolized pentamidine. Am J Med 1990;88:53N 56N. 46. Anagnostopoulos GK, Tsiakos S, Margantinis G, et al. Acute pancreatitis due to pravastatin therapy. J Pancreas (online) 2003;4: Available at: Blake WE, Pitcher ME. Estrogen-related pancreatitis in the setting of normal plasma lipids: case report. Menopause 2003;10: Falko JM, Thomas FB. Acute pancreatitis due to procainamideinduced lupus erythematosus. Ann Intern Med 1975;83: Straumann A, Bauer M, Pichler WJ, et al. Acute pancreatitis due to pyritinol: an immune-mediated phenomenon. Gastroenterology 1998;115: Ceciliato R, Pezzili R, Barakat B, et al. Acute pancreatitis due to simvastatin therapy: increased severity after re-challenge. JOP J Pancreas (online) 2004;5(Suppl):411. Available at: Barret PVD, Their SO. Meningitis and pancreatitis associated with sulfamethazole. N Engl J Med 1963;268: Brazer SR, Medoff JR. Sulfonamide induced pancreatitis. Pancreas 1988;3: Gasser R, Magill AJ, Oster CN, et al. Pancreatitis induced by pentavalent antimonial agents during treatment of leishmaniasis. Clin Infect Dis 1994;18: Klein SM, Khan MA. Hepatitis, toxic epidermal necrolysis and pancreatitis in association with sulindac. J Rheumatol 1983; 10: Zygmunt D. Acute pancreatitis with long term sulindac. West J Med 1986;44: Memon A. Sulindac induced acute pancreatitis. Ann Intern Med 1982;97: Torosis J, Vender R. Tetracycline induced acute pancreatitis. J Clin Gastroenterol 1987;9: Elmore MF, Rogge JD. Tetracycline induced pancreatitis. Gastroenterology 1981;81: Antonow DR. Acute pancreatitis associated with trimethoprimsulfamethoxazole. Ann Intern Med 1986;104: Coulter DL, Allen RJ. Pancreatitis associated with valproic acid therapy for epilepsy. Ann Neurol 1980;7: Camfield PR. Pancreatitis due to valproic acid. Lancet 1979;i: Fecik SE, Stoner SC, Raphael J, et al. Recurrent acute pancreatitis associated with valproic acid use for mood stabilization. J Clin Psychopharmacol 1999;19: Rominger JM, Gutierrez JG, Curtis D, et al. Methyldopa induced pancreatitis. Dig Dis 1978;23: Warren SE, Mitas JA, Swerdlin AHR. Pancreatitis due to methyldopa: case report. Mil Med 1980;145: Abou Chacra L, Ghosn M, Ghayad E, et al. A case of pancreatitis associated with all-trans-retinoic acid therapy in acute promyelocytic leukemia. Hematol J 2001;2: Yutsudo Y, Imoto S, Ozuru R, et al. Acute pancreatitis after all-trans retinoic acid therapy. Ann Hematol 1997;74: Izumi T, Hatake K, Miura Y. Acute promyelocytic leukemia. N Engl J Med 1994;330: Fiorentini MT, Fracchida M, Galatola G, et al. Acute pancreatitis during oral 5-aminosalicylic acid therapy. Dig Dis Sci 1990;35: Erdkamp F, Houben M, Ackerman E, et al. Pancreatitis induced by mesalamine. Neth J Med 1992;41: Isaacs KL, Murphy D. Pancreatitis after rectal administration of 5-aminosalicylic acid. J Clin Gastroenterol 1990;12: Block MB, Genant HK, Kirsner JB. Pancreatitis as an adverse reaction to salicylazosulfapyridine. N Engl J Med 1970;282: Adachi E, Okazaki K, Matsushima Y, et al. Acute pancreatitis secondary to 5-aminosalicylic acid therapy in a patient with ulcerative colitis. Int J Pancreatol 1999;25: Fernandez J, Sala M, Panes J, et al. Acute pancreatitis after