Nonsteroidal Anti-Inflammatory Drug-Induced Hepatic Disorders

PHARMACOEPIDEMIOLOGY Drug Safety 1996 Jul; 15 (I); 64-71 0114-5916/96/OOO7-0064/S04.OO/0

© Adis International limited. All rights reserved.

Nonsteroidal Anti-Inflammatory Drug-Induced Hepatic Disorders Incidence and Prevention

Aram V Manoukian1 and Jeffrey L. Carson2

1 The Division of Gastroenterology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA

2 The Division of General Internal Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA

Contents Summary , ................ 64 1. Study Design ............... 65 2. Definition of Drug-Induced Liver Injury . 65 3. Cohort and Case-Control Studies 66 4. Clinical Descriptions 67

4.1 Sulindac .... 67 4.2 Diclofenac. . . 68 4.3 Indomethacin . 68 4.4 Ibuprofen 69 4.5 Naproxen ... 69 4.6 Oxaprozin ... 69 4.7 Phenylbutazone 69 4.8 Other Nonsteroidal Anti-Inflammatory Drugs 69

5. Risk Factors 6. Prevention . 7. Conclusion

Summary

69 70 70

The nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequently used medications worldwide for the treatment of a variety of common chronic and acute inflammatory conditions. The association between NSAIDs and liver disease is poorly documented, the exceptions being sulindac and, to a lesser degree, diclofenac.

The incidence of liver disease is very low and is relatively unimportant compared with the risk of peptic ulcer disease and gastrointestinal bleeding. Reports of hepatic injury range from insignificant and transient liver enzyme elevation to severe and fulminant hepatitis.

It has been estimated that approximately 3 million people in the US take nonsteroidal anti-inflammatory drugs (NSAIDs) on a daily basis. This popular, heterogenous group of compounds provides

relief from a variety of acute and chronic conditions by way of their antipyretic, analgesic and anti-inflammatory properties. However, many clinical reports have suggested that these agents have some

NSAID-Induced Hepatic Disorders

hepatotoxic effects. In some cases, these are mild and transient, or in the most severe cases, they culminate in fulminant hepatic failure.

The purpose of this review is to describe the evidence linking NSAIDs with acute liver injury, and when possible, to describe the clinical characteristics of patients with liver injury from individual NSAIDs. We will begin by very briefly describing the types of studies that have been used to link NSAIDs with Ii ver disease. We will then review the cohort and case-control studies that describe this association and describe what is known about the incidence and risk factors of liver disease in patients taking NSAIDs. There then follow clinical descriptions from case reports and case series of patients taking NSAIDs who developed liver disease. We focus on those case series with an adequate number of patients to provide a good clinical description, and make no attempt to be comprehensive. Single case reports are cited if recurrent hepatitis occurred on rechallenge with the drug. Finally, we will conclude with a summary and recommendations on monitoring patients for liver disease who are taking NSAIDs.

1. Study Design

The study designs available to assess the adverse effects of medication include: • randomised, controlled trials • cohort studies • case-control studies • case series • case reports.

Conducting a randomised, placebo-controlled trial is the best way to determine the incidence of adverse reactions to a medication and its causal relationship. However, these studies are often impractical because very large numbers of patients are needed to accurately assess infrequent adverse effects.

In a cohort study, exposed and non-exposed patients are followed for liver complications. This is often performed by using large pharmacy or insurance databases. In a case-control study, the prevalence of drug exposure in patients with the outcome

© Adis Internotionollirnited. All rights reserved.

65

of interest (cases) is compared with that in a control population. Both cohort and case-control studies are subject to selection bias and confounding. NSAID users and nonusers are likely to differ in many important ways, such as in alcohol use, comorbidity, and other drug use. In some studies, it may be difficult to measure or control for some of these confounding factors.

Case series or reports describe patients who develop a disease after exposure to a drug. Because there is no control group, it is possible that the drug is not causally related to the disease and just an incidental finding. Furthermore, since the number of patients exposed to the drug is unknown, it is impossible to calculate the incidence. Profiles of drugs showing a disproportionate number of reports of liver disease may suggest a problem, but must be interpreted cautiously. Case series and reports are the weakest type of epidemiological evidence. However, if patients are rechallenged with a drug and the same adverse reaction occurs, this strongly suggests a causal association. For rare diseases such as liver disease, case reports may be the only feasible way of detecting adverse drug reactions.

2. Definition of Drug-Induced Liver Injury

Criteria for drug-induced liver disorders have only recently been developed by an international consensus panel,[l] and many studies have not used them. Since histological data are often not available, the criteria focus on laboratory and clinical information.

Liver injury is defined as an increase in ALT or conjugated bilirubin to twice the normal range, or a combined increase in serum levels of AST, alkaline phosphatase and total bilirubin, provided that one is above 2 times the normal range. Hepatocellular injury is defined as an increase in serum ALT level of greater than 2 times normal, or a ratio of ALT : alkaline phosphatase> 5. Each laboratory test is expressed as a multiple of normal. Cholestatic injury is presumed to occur when the alkaline phosphatase level is over 2 times normal, or the

Drug Safety JuI1996; 15 (1)

66

ratio of ALT : alkaline phosphatase ratio < 2. A mixed pattern is present when both ALT and alkaline phosphatase are over 2 times normal and the ALT divided by alkaline phosphatase ratio is > 2 and < 5.

Liver injury is designated acute if present for less than 3 months and chronic if present for greater than 3 months. Severe injury is associated with jaundice, prothrombin time >50% of normal or hepatic encephalopathy.

Causation assessments are made by determining the time interval to the onset of the reaction, the course of reaction, the effect of rechallenge with the drug, and the presence of other risk factors for liver disease. These definitions were used in some of the studies described below.

3. Cohort and Case-Control Studies

There have been 7 cohort or case-control studies that have evaluated the incidence and association of NSAIDs and liver disease. Johnson et al.[2] did a search of a health maintenance organisation database for hospitalisations 3 months after ibuprofen was dispensed to 13 230 members under 65 years of age. The computer printouts, which included the discharge diagnoses and surgical procedures, were reviewed. Patients were excluded from further consideration if the admission was related to illness associated with an indication for ibuprofen such as arthritis, the illness had an aetiology unlikely to be related to NSAIDs (e.g., orthopaedic surgery), or the illness developed prior to the prescription for ibuprofen. The medical records of the remaining patients were then reviewed. None of the patients dispensed ibuprofen were hospitalised for liver disease. In a similar study, no patient exposed to ibuprofen or indomethacin was hospitalised with drug-induced liver disease)3]

Jick and colleagues[4] evaluated the development of liver disease in 102 644 patients taking diclofenac, naproxen or piroxicam. Case histories of patients with a diagnosis of liver disease were reviewed by 2 medically trained epidemiologists to determine the causal relationship between liver disease and NSAID exposure. A causal relationship


Manoukian & Carson

was considered definite if, on rechallenge, the NSAID caused liver disease. A causal relationship was considered probable if a diagnosis of NSAIDinduced liver disease was diagnosed by the general practitioner or consultant. A causal relationship was considered possible if there was a temporal relationship between NSAID exposure and no other likely cause of liver disease was present. Only 1 probable case and 10 possible cases of NSAID-induced liver disease were identified in over 100 000 patients.

Garcia Rodriguez et aI.l5] performed a retrospective cohort study in 228 392 adults who were dispensed diclofenac, indomethacin, sulindac, naproxen or piroxicam, using record linkage data from Saskatchewan, Canada. Patients who received one of the study NSAIDs were followed until the development of hepatitis, death, withdrawal from the health plan or the end of the study. Patients were considered to be exposed to a drug for 60 days following prescription of the NSAID. Medical records of patients with an International Classification of Diseases (ICD) code consistent with acute hepatitis were reviewed for alternative diagnoses including alcoholism, cancer, gallstones, viral hepatitis (hepatitis C testing was not available at the time of this study), chronic liver disease, blood transfusion and other diseases that could explain hepatitis. The incidence rate among current users was 9 [95% confidence interval (CI) 6 to 15] per 100000 person years. The unadjusted relative risk was 2.3 (95% CI 1.1 to 4.9), and there was an excess risk of 5 cases per 100 000 person years. However, with adjustment for age and gender the relative risk of 1.7 (95% CI 0.8 to 3.7) was no longer significant. In the absence of any other hepatotoxic drugs, the relative risk increased to 4.0 (95% CI 0.9 to 19.0). No dosage or duration effect was seen.

Perez Gutthan and Garcia Rodriguez[6] performed a second analysis using the same data described above. A nested case-control study was performed, in which exposure to NSAIDs and other hepatotoxic drugs was assessed in patients with liver disease and a random sample of 500 healthy individuals without liver disease. As before, exposure was defined by prescription 60 days prior to index date.

Drug Safety JuI1996; 15 (1)


Exposure to NSAIDs alone was not associated with liver disease; odds ratio 2.1 (95% CI 0.6 to 7.0). However, exposure to other known hepatotoxic drugs was associated with liver disease; odds ratio 6.9 (95% CI 2.5 to 19.4). The risk of liver disease was even higher if patients were taking both NSAIDs and other hepatotoxic drugs; odds ratio 11.6 (95% CI 4.2 to 32.9). This interaction suggests that patients taking NSAIDs simultaneously with other hepatotoxic drugs are at greater risk of liver disease than if only taking an NSAID alone. In the analysis of individual drugs, only sulindac was associated with a significantly elevated risk; odds ratio 5.0 (95% CI 1.3 to 18.5).

Carson and colleagues[7] performed a case-control study using Medicaid billing data. The medical records of potential cases admitted to the hospital with an ICD code consistent with hepatitis were reviewed to validate the diagnosis, and to identify alternative causes of liver disease [alcoholism, viral hepatitis (hepatitis C testing was not available at the time of the study), cancer, blood product transfusion, chronic disease]. There were 107 patients with symptomatic acute hepatitis without an identifiable cause of liver disease. No association between liver disease and NSAIDs was identified; adjusted odds ratio was 1.2 (95% CI 0.5 to 2.8). The risk appeared elevated with sulindac (odds ratio 4.1, 95% CI 0.8 to 22.4), although it was not statistically significant. The annual incidence of acute idiopathic symptomatic hepatitis resulting in hospitalisation was very low; 2.2 (95% CI 2.0 to 2.4) per 100 000 patients per year.

Garcia Rodriguez et al. [8] performed a second retrospective cohort study using General Practice Research Database (formerly known as VAMP) record linkage data from 536 general practitioners' offices in England and Wales from 1987 to 1991. 625 307 patients who received more than 2 million prescriptions for one of 12 NSAIDs were followed for the development of acute liver disease. Liver disease was considered in all patients with a OXMIS diagnosis related to liver disease. OXMIS Problem Codes for Primary Medical Care, Oxford, England, was the diagnosis code system used in the

© Adis International Limited. All rights reserved.

67

database. Cases were confirmed by medical record review and patients with other causes of liver disease were excluded. Only 23 cases of acute liver disease occurred, yielding an incidence of 3.7 (95% CI 2.5 to 5.5) per 100000 NSAID users or 1.1 (95% CI 0.7 to 1.6) per 100000 NSAID prescriptions. The incidence rate was similar for all NSAIDs except sulindac, which had an incidence rate of 148.1 (95% CI 50.4 to 434.7) per 100000 users and 27.2 (95% CI 9.3 to 80.1) per 100 000 prescriptions. However, these results were only based on 3 cases of liver disease in patients taking sulindac. Use of other hepatotoxic drugs and presence of rheumatoid arthritis were risk factors for acute liver disease, while age and gender were not associated with liver disease. This study did not include a control group of unexposed patients.

Cohort and case-control studies have not found a consistent relationship between NSAIDs and liver disease. One study found a borderline association between NSAIDs.l5] However, 2 studies found an elevated risk with NSAIDs when used with other hepatotoxic drugs.[6,8] Three studies found evidence that sulindac had the highest risk of liver disease among the NSAIDs.[6-8] However, even if we assume that there is a causal relationship between some NSAIDs and liver disease, the most important finding from these studies is that the incidence of liver disease from NSAID therapy is extremely low.

4. Clinical Descriptions

4.1 Sulindac

The strongest evidence linking NSAIDs with liver disease is for sulindac. Multiple reports have reported sulindac therapy leading to hepatitis on rechallenge.l9- 17] Previously cited data found that the incidence of acute liver injury was 148.1 per 100 000 sulindac users and 27.2 per 100 000 sulindac prescriptions (see section 3).[6] An association with liver disease was found in one study (odds ratio 5.0, 95% CI 1.3 to 18.5)[6] and was borderline in a second study (odds ratio 4.1, 95% CI 0.8 to 22.4),17]

Drug Safety Jul 1996; 15 (1)

68

Tarazi and coworkers[ 181 published an analysis of 91 cases of sulindac-induced hepatic injury reported to the US Food and Drug Administration (FDA). During the years 1978 through 1986,338 reports of presumed hepatobiliary injury were submitted to the FDA. Excluded were 247 of these cases since the data reported were either unconvincing or inadequate to assume causation. The clinical syndrome was described from the remaining patients who were thought to have sulindac-induced hepatotoxicity.

In this study,[ 181 the onset of clinical illness was noted within 4 weeks of exposure in 48%, with 30% developing a reaction to sulindac in 4 to 8 weeks. Hepatic injury developed in 22% of patients after 8 weeks. Of the patients reviewed, 69% were more than 50 years of age, with only 6% below 20 years of age. The majority of the patients were women, and the female: male ratio was significant at 3.5 : I. Nausea and vomiting were the most frequently occurring symptoms (67% of patients), followed by fever (55%), rash (48%) and jaundice-associated pruritus (40%). The most frequently reported sign was jaundice (67%). The most common liver enzyme pattern was cholestatic, reported in 43% of patients, and a hepatocellular pattern was seen in 25%.

The clinical hallmarks of a hypersensitivity reaction (fever, rash and peripheral eosinophilia) were reported in 35 to 55% of patients. Peripheral eosinophilia was found in 35% of patients, and occurred most commonly in those with a cholestatic liver enzyme pattern (40%). Positive rechallenge with sulindac was documented in 13 patients and hepatic injury recurred in each case. Four of the 91 patients died, 3 from severe hypersensitivity, and 1 from fulminant hepatic failure .

4.2 Diclofenac

Diclofenac has been suggested to cause hepatic injury of a mixedlhepatocellular type, and fulminant hepatic failure.[I9-221 15% of patients who use diclofenac develop elevations in transaminase values of up to 3 times the upper limit of normaJ.l231


Manoukian & Carson

The records of all cases reports of hepatic dysfunction sent to the Australian Adverse Drug Reactions Advisory Committee from 1981 to 1989 were reviewed by Purcell and Henry.[241 Only 26 of 82

patients with suspected diclofenac-induced hepatotoxicity were thought to have this drug as the sole cause of liver injury. The average age of these 26 patients was 64 (range 37 to 84) years and 70% were women. The symptoms included jaundice (57%), anorexia (23%), nausea (23%) and hepatic pain (15%). Notably, 25% of all the patients were asymptomatic. Hypersensitivity symptoms were absent.

In this study,[241 the predominant pattern of liver

function test abnormalities was an elevation of transarninases. A spectrum of severity was identified, with liver chemistry varying from minor transaminase elevations to a 40-fold rise in these parameters. In most patients, liver enzymes normalised after the discontinuation of diclofenac. Most cases occurred within the first 6 months of therapy and the median cumulative dose of drug was 8.7g. A correlation was noted between the cumulative dose received by the patient and the severity of liver damage assessed by the peak transaminase concentration.

The above data suggest that impaired clearance of a metabolite could be the mechanism of injury. Only I patient died from massive hepatic necrosis in that study,[241 although 15 deaths were reported by the manufacturer, Ciba-Geigy, to the FDA in 1988, over the l4-year period the drug was studied. In that report 408 hepatic reactions were noted. There are 2 case reports in which patients rechallenged with diclofenac developed recurrent liver disease,l25,261

4.3 Indomethacin

Indomethacin has rarely been described as a cause of hepatotoxicity, although cases of fulminant hepatitis have been seen.[27-291 Initially thought to cause

only hepatocellular damage, cholestatic liver injury is also seenP6-281

Drug Safety Jull996: 15 (1)


4.4 Ibuprofen

Early reports with ibuprofen suggest that approximately 4% of all adverse reactions involve the liver.l30] However, no deaths occurred from liver disease in over 400 reports reviewed. Liver chemistry elevations have been noted in some,[31] but not all, reports,l32]

The incidence of acute liver injury is 1.6 per 100000 users (95% CI 0.7 to 3.8) and 0.7 per 100 000 prescriptions (95% CI 0.3 to 1.6).17] A mixed cholestatic or hepatocellular pattern is the most frequent liver chemistry finding.[33-35] The mechanism of hepatotoxicity is unclear. Although the clinical features of the condition implicate immunological idiosyncrasy,[36] suggestions of metabolic mediation[37] or intrinsic toxicity[38] have also arisen.

4.5 Naproxen

Naproxen is a rare cause of clinical liver disease, although at least 2 studies estimate the incidence of abnormal liver enzymes to be approximately 4%.[39,40] Clinical jaundice is an uncommon

event having been reported in approximately 5 patients.[41-45] The incidence of acute liver injury is 3.8 per 100000 users (95% CI 1.5 to 9.9) and 1.5 per 100000 prescriptions (95% CI 0.6 to 3.8).[7] No confirmed liver-related mortality resulting from therapy with the agent has been described.[46] In the studies in which jaundice developed, its onset began within several months of the initiation of therapy.l41.44] Once discontinued, the clinical response was rapid, with resolution of jaundice within 1 month.l41 -44] The mechanism of injury is unknown.

4.6 Oxaprozin

Oxaprozin has been noted to cause elevations in liver chemistry in up to 15% of those using the medication.l47] A recent study reviewed the adverse effects of oxaprozin on the liver in 1338 patients with various rheumatic diseases.[48] It was found that serum AST levels rose in 15.4% of patients, but elevations greater than 3 times normal were seen in only 1.1 % of recipients. In 50% of affected patients, normalisation of these biochemical parameters


69

occurred, despite continuation of oxaprozin; this indicates either the development of tolerance or that the drug was not responsible for the abnormal liver tests. Only 1 patient, or less than 0.1 % of the total group receiving the medication, developed anicteric hepatitis . Metabolic idiosyncrasy has been implicated as the mechanism of hepatic injury with the use of oxaprozin.

4.7 Phenylbutazone

Phenylbutazone is estimated to be associated with abnormal liver enzyme levels in I to 5% of patients. [49] Most patients show signs of hepatocellular damage resembling viral hepatitis, although a significant minority show a more cholestatic picture.l50]

The characteristics of phenylbutazone-induced hepatotoxicity were reviewed in 23 well-documented cases and 43 reports in the literature. [49] Over 85% of these patients were over 30 years of age, with 30% over the age of 60 years. The gender distribution was equal in this case series. Approximately 60% of patients developed hepatic injury within 6 weeks of the onset of therapy. The presence of fever and rash in 60% of patients suggests that hypersensitivity is the mechanism of injury; hepatic granulomas were found in approximately one-third of liver biopsies from these patients. The mortality in this case series was between 22 and 28%.

4.8 Other Nonsteroidal Anti-lnflammtory Drugs

Tolmetin has rarely been reported to cause hepatic toxicity.l51 .52] Hepatotoxicity associated with piroxicam has recently been reported in 3 case reports.[53-58] Abnormal liver chemistry has been described with mefenamic acid and meclofenamic acid, but this is usually transient, and normalises despite the continuation of therapy with these agents.[59]

Fenoprofen, ketoprofen and flurbiprofen have not been reported to cause hepatotoxicity.

5. Risk Factors

Several studies have evaluated the risk factors for developing NSAID-induced liver disease. The

Drug SafetyJul 1996: 15(1)

70

results of studies by Garcia Rodriguez et aP5] and Perez Gutthan and Garcia Rodriguez[6] showed that the risk of liver disease associated with NSAIDs was increased when the patient was also taking another hepatotoxic drug. In the first study, the relative risk was 4.0 (95% CI 0.9 to 19.0) in patients taking NSAIDs with no concornittant use of hepatotoxic drugs. In the second study, the odds ratio for patients taking NSAIDs and other hepatotoxic drugs was increased to 11.6 (95% CI 4.2 to 32.9). In contrast, Carson et al.[7] found that the odds ratio was only 2.1 (95% CI 0.6 to 5.8) in patients taking NSAIDs and other hepatotoxic drugs.

Garcia Rodriguez and colleagues[8] also found that patients with rheumatoid arthritis had an elevated risk of 10.9 (95% CI 2.4 to 50.2) compared with patients with osteoarthritis. Age or gender was not a risk factor in any of the studies. It is important to note that all the studies excluded patients with chronic liver disease and heavy alcohol use, so there is no information available on the use of NSAIDs in those clinical settings.

6. Prevention

Several strategies should be used to prevent NSAID-induced liver disease. When possible, physicians should avoid prescribing other hepatotoxic drugs at the same time as NSAIDs. In those patients with pre-existing chronic liver disease or with a history of heavy alcohol use, NSAIDs should be used with caution and only in those with minimal hepatic insufficiency, since there is little data documenting their safety. It also would be prudent to use one of the NSAIDs with the least potential for hepatic injury and to monitor the patient monthly. If liver chemistry worsens over baseline or clinically apparent injury develops (symptoms or jaundice), the medication should be discontinued and the patient's progress followed carefully.

While it would be possible to monitor liver enzyme tests regularly in patients dispensed a NSAID, this may not be cost effective. Even with sulindac, where the evidence is most secure and the incidence the highest (148 per 100000 patients), 676 patients would need to be tested to find one signif-


Manoukian & Carson

icant case of liver disease. Therefore, it seems most reasonable to inform the patient that liver disease may occur rarely, and if the patient develops any new symptoms to immediately bring it to the attention of the physician and to stop the drug. Liver enzymes should then be measured. Certainly, if symptoms of hepatocellular injury, jaundice, or hypersensitivity develop, this should also prompt cessation of therapy.

7. Conclusion

The strongest evidence linking NSAIDs with liver disease is for sulindac. While cohort and casecontrol studies only show a borderline association, the multiple case reports with rechallenge suggest a causal relationship. There are also a significant number of reports of hepatotoxicity on rechallenge with diclofenac. The evidence linking the other NSAIDs to liver disease is weak, although when NSAIDs are used with other hepatotoxic drugs, the risk appears to be high. However, the incidence of liver disease, if you accept that an association exists, is very low and relatively unimportant compared with the risk of peptic ulcer disease and gastrointestinal bleeding that result from the use of this class of drugs.

References I. Benschou c. Criteria of drug induced liver disorders: report of

an international consensus meeting. J Hepatol 1990; II: 272-6 2. Johnson JH, Jick H, Hunter JR, et al. A follow-up study of

ibuprofen users. J Rheumatol 1986; 12: 549-52 3. Beard K, Belic L, Aselton P, et al. Outpatient drug-induced pa

renchymalliver disease requiring hospitalization. J Clin Pharmacol 1986; 26: 633-7

4. Jick H, Derby LE, Garcia Rodriguez LA, et al. Liver disease associated with diclofenac, naproxen and piroxicam. Pharmacotherapy 1992; 12: 207-12

5. Garcia Rodriguez LA, Perez Gutthan S, Walker AM, et al. The role of non-steroidal anti-inflammatory drugs in acute liver disease. BMJ 1992; 305: 865-8

6. Perez Gutthan S, Garcia Rodriguez LA. The increased risk of hospitalizations for acute liver injury in a population with exposure to multiple drugs. Epidemiology 1993; 4: 496-501

7. Carson JL, Strom BL, Duff A, et al. Safety ofNSAIDs with respect to acute liver disease. Arch Intern Med 1993; 153: 1331-6

8. Garcia Rodriguez LA, Williams R, Derby LE, et al. Acute liver injury with nonsteroidal anti-inflammatory drugs and the role of risk factors. Arch Intern Med 1994; 154: 311-6

9. Daniele B, Pignata S, D' Agostino L, et al. Sulindac-induced severe hepatitis. Am J Gastroenterol 1988; 83: 1429'31

Drug Safety Jul 1996: 15 (l)


10. Dhand AK, LaBrecque DR, Metzger J. Sulindac (Clinoril) hepatitis. Gastroenterology 1981; 80: 585-6

II. Whittaker SJ, Amar IN, Wanless IR, et al. Sulindac hepatotoxicity. Gut 1982; 23: 875-7

12. Lerche A, Vyberg M, Kirkegaard E. Acute cholangitis and pancreatitis associated with sulindac (Clinoril). Histopathology 1987; II: 647-53

13. Smith FE, Lindberg PPJ. Life-threatening hypersensitivity to sulindac. JAMA 1980; 244: 269-70

14. Groux Y, Moreau M, Kass TG. Cholestatic jaundice caused by sulindac. Can J Surg 1982; 25 : 334-5

IS. Kaul A, Reddy JC, Fagman E, et al. Hepatitis associated with use of sulindac in a child. J Pediatr 1981; 99: 650-1

16. Park GD, Spector R, Headstream T, et al. Serious adverse reactions associated with sulindac. Arch Intern Med 1982; 142: 1292-4

17. Wood LJ, Searle J, Mundo F, et al. Sulindac hepatotoxicity: effects of acute and chronic exposure. Aust N Z J Med 1985; 15: 397-401

18. Tarazi EM, Harter JG, Zimmerman HJ, et al. Sulindac-associated hepatic injury analysis of 91 cases reported to the Food and Drug Administration. Gastroenterology 1993; 104: 569-74

19. Breen EG, McNicholl J, Cosgrove E, et al. Fatal hepatitis associated with diclofenac. Gut 1986; 27: 1390-3

20. Schapira D, Bassan L, Nahir AM, et al. Diclofenac-associated hepatotoxicity. Postgrad Med J 1986; 62: 63-5

21. Lasgar G, Grippon P, Levy VG. Acute fatal hepatitis during treatment with diclofenac. Gastroenterol Clin Bioi 1984; 8: 881-2

22. Babany G, Bernuau J, Danan G, et al. Hepatite fulminante chez une femme prenant de la glafenine et de diclofenac [letter] . Gastroenterol Clin Bioi 1985; 9: 185

23. Voltaren: diclofenac sodium. The number one antiarthritic in the world. Ciba-Geigy, 1981 Aug

24. Purcell P, Henry D, Melville G. Diclofenac hepatitis. Gut 1991; 32: 1381-5

25. He1fgott SM, Sandberg-Cook J, Zakim D, et al. Diclofenacassociated hepatotoxicity. JAMA 1990; 264: 2660-2

26. Dunk AA, Walt RP, Jenkins WJ, et al. Diclofenac hepatitis. BMJ 1982; 284: 1605-6

27. Kelsey WM, Scharyj M. Fatal hepatitis probably due to indomethacin. JAMA 1967; 199: 586-7

28. Jacobs Je. Sudden death in arthritic children receiving large doses of indomethacin. JAM A 1967; 199: 932-4

29. Fenech FF, Bannister WH, Grech JL. Hepatitis with biliverdinaemia in association with indomethacin therapy. BMJ 1967; 3: 155-6

30. Cuthbert MF. Adverse reactions to nonsteroidal antirheumatic drugs. Curr Med Res Opin 1974; 2: 600-10

31. Boyer GL, Seckman CE, Welschman IR. Safety profile: fifteen years of clinical experience with ibuprofen. Am J Med 1984; 77: 25-34

32. Freeland GR, Northington RS, Hedrich DA, et al. Hepatic safety of two analgesics used over the counter: ibuprofen and aspirin. Clin Pharmacol Ther 1988; 43: 473-9

33. Lewis JH. Hepatic toxicity of nonsteroidal anti-inflammatory drugs. Clin Pharm 1984; 3: 128-38

34. Stempel DA, Miller 11. Lymphopenia and hepatic toxicity with ibuprofen. J Pediatr 1977; 90: 657-8

35. Zimmerman HJ, Maddrey We. Toxic and drug induced hepatitis. In: SchiffL, SchiffER, editors. Diseases of the liver, 7th ed. Philadelphia: JB Lippencott, 1993: 707-83

36. Stricker BHC, Spoelstra P. Drug-induced liver injury. Amsterdam: Elsevier, 1985: 45-76


71

37. Bravo JF, Jacobson MP, Mertens BF. Fatty liver and pleural effusion with ibuprofen therapy. Ann Intern Med 1977; 87: 200-1

38. Lee CY, Finkler A. Acute intoxication due to ibuprofen overdose. Arch Pathol Lab Med 1986; 110: 747-9


40. Barron KS, Person DA, Brewer EJ. The toxicity of nonsteroidal anti-inflammatory drugs in juvenile rheumatoid arthritis. J Rheumatol 1982; 9: 149-55

41. Stricker BHC, Spoelstra P. Drug-induced liver injury. Amsterdam: Elsevier, 1985: 45-76

42. Bass BH. Jaundice associated with naproxen [letter]. Lancet 1974; I: 998

43. Victorino RMM, Silvera JCB, Baptista A, et al. Jaundice associated with naproxen . Postgrad Med J 1980; 56: 368-70

44. Law IP, Knight H. Jaundice associated with naproxen [letter]. N Engl J Med 1976; 295: 1201

45. Lagarriga J. Naproxen e icteria [letter]. Rev Scand Milit 1975; 29:250


47. Zimmerman HJ. Update of hepatotoxicity due to classes of drugs in common use: nonsteroidal drugs, anti-inflammatory drugs, antibiotics, antihypertensives and cardiac and psychotropic drugs. Semin Liver Dis 1990; 10: 322-38

48. Zimmerman HJ. Hepatic effects of oxaprozin. Semin Arthritis Rheum 1986; 15 (3) Suppl. 2: 35-9


50. Benjamin SB, Ishak KG, Zimmerman HJ, et al. Phenylbutazone liver injury: a clinical-pathologic survey of 23 cases and review of the literature. Hepatology 1981; I: 255-63

51. Brogden RN, Heel RC, Speight TM, et al. Tolmetin: a review of its pharmacological properties and therapeutic efficacy in rheumatic diseases. Drugs 1978; 15: 429-50

52. Craig GL, Buchanan Ww. Antirheumatic drugs: clinical pharmacology and therapeutic use. Drugs 1980; 20: 453-84

53. Hartman H. Prolonged cholestatic jaundice and leukopenia associated with piroxicam. Gastroenterology 1984; 22: 343-5

54. Lee SM, O'Brien CJ, Williams R, et al. Subacute hepatic necrosis induced by piroxicam. BMJ 1986; 293: 540-1

55. Bismuth H, Samuel D, Gugenheim J, et al. Emergency liver transplantation for fulminant hepatitis. Ann Intern Med 1987; 107: 337-41

56. Planas R, Leon RD, Quer JC, et al. Fatal submassive necrosis of the liver associated with piroxicam. Am J Gastroenterol 1990; 85: 468-70

57. Caballeria E, Masso RM, Arago JV, et al. Piroxicam hepatotoxicity. Am J Gastroenterol 1990; 85: 898-9

58. Hepps KS, Maliha GM, Estrada R, et al. Severe cholestatic jaundice associated with piroxicam. Gastroenterology 1991; 101: 1737-40


Correspondence and reprints: Dr Jeffrey L. Carson, Division of General Internal Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 125 Paterson Street, New Brunswick, NJ 08903, USA.

Drug Safety JuI1996: 15 (1)

Documents

Nonsteroidal Anti-Inflammatory Drug-Induced Hepatic Disorders