Risk of Acute Liver Injury Associated with the Use of Drugs: a Multicentre Population Survey M

Alimentary Pharmacology & Therapeutics

Risk of acute liver injury associated with the use of drugs: a multicentre population survey M. SABATE´ *, L. IBA´ N˜ EZ*, E. PE´ REZ*,X.VIDAL*,M.BUTI ,X.XIOLà, A. MAS§, C. GUARNER–, M. FORNE´ **, R. SOLA` ,J.CASTELLOTEà,J.RIGAUàà & J.-R. LAPORTE*

*Fundacio´ Institut Catala` de Farmaco- SUMMARY logia, Universitat Auto`noma de Barcelona, Hospital Vall d’Hebron, Background Barcelona; Liver Unit, Hospital Acute liver injury of uncertain aetiology is often drug related and quan- Vall d’Hebron, Barcelona; àGastroenterology Service, Hospital titative information about the associated risk is scarce. Prıńceps d’Espanya de Bellvitge, Hospitalet de Llobregat; §Liver Unit, Aim Hospital Clıńic, IDIBAPS, Barcelona; To estimate the risk of acute liver injury associated with the use of –Gastroenterology Service, Hospital drugs. de la Santa Creu i Sant Pau, Barcelona; **Gastroenterology Service, Methods Hospital de Mu´tua, Terrassa; Liver section, Hospital del Mar, In a population survey study, 126 cases of acute liver injury were pro- Universitat Auto`noma de Barcelona; spectively assembled from January 1993 to December 1999, in patients ààGastroenterology Service, Hospital over 15 years of age, in 12 hospitals in Barcelona (Spain). We estimated General, Granollers the relative risk for each drug as the ratio between the incidence of Correspondence to: acute liver injury among the exposed population to the drug and the Dr M. Sabate´, Fundacio´ Institut Catala` incidence of acute liver injury among those not exposed to it. Drug de Farmacologia, P Vall d’Hebron consumption data were used to estimate the exposed population. 119-129, 08035 Barcelona, Spain. E-mail: [email protected] Results Isoniazid, pyrazinamide, rifampicin, amoxicillin with clavulanic acid, Publication data erythromicin, chlorpromazine, nimesulide, and ticlopidine presented the Submitted 20 November 2006 highest risk (point relative risk > 25). Amoxicillin, metoclopramide, cap- First decision 25 December 2006 Resubmitted 23 March 2007 topril and enalapril, furosemide, hydrochlorothiazide, fluoxetine, par- Accepted 4 April 2007 oxetine, diazepam, alprazolam, lorazepam, metamizole, low-dose acetylsalicylic acid and salbutamol showed the lowest risk (point relative risk < 5).

Conclusions This study provides a risk estimation of serious liver disease for various drugs that will be useful in its diagnosis and management, and when comparing with the drug therapeutic beneﬁt in each indication. Some observed associations would be worth speciﬁc studies.

Aliment Pharmacol Ther 25, 1401–1409

ª 2007 The Authors 1401 Journal compilation ª 2007 Blackwell Publishing Ltd doi:10.1111/j.1365-2036.2007.03338.x 1402 M. SABATE´ et al.

alkaline phosphatase of at least two-fold the upper INTRODUCTION limit of the normal range. Patients with other possible Acute liver injury (ALI) of uncertain aetiology is often causes of liver injury were excluded (Table 1). Patients related to exposure to potentially hepatotoxic agents. with biliary lithiasis, but without enlargement of the In the last 30 years, it has been the leading cause of main biliary duct and clinical presentation and course withdrawal of medicines from the market.1 not suggestive of biliary colic, were included. In these Most of the information on drug liver injury comes cases, an endoscopic retrograde cholangiopancreatog- from case histories or from registries of spontaneous raphy had to be performed in order to exclude the reports of adverse reactions.2 Several epidemiological obstruction of the biliary tree. studies have been published.3–8 However, quantitative information about the risk of ALI associated with the Drugs of interest most widely used drugs is relatively scarce,4, 5, 7 even for older drugs. With the aim of estimating the risk of Drug exposures were considered if they had taken ALI associated with the use of drugs, we performed a place within 15 days (hepatocellular pattern) or case–population study on ALI unrelated to infectious, 30 days (acute cholestatic or mixed pattern) before the obstructive or metabolic disease in a well-defined area onset of the symptoms of liver disease (aetiological in Barcelona (Spain). period). 11 For estimation of the RR, drugs with three or more exposed cases with the same liver pattern were consid- METHODS ered. We did a multicentre prospective case–population study, with systematic ascertainment of all incident Data analysis cases of ALI, irrespective of the suspected cause. The relative risk (RR) was estimated by the case–population In a case–control study, previous exposures among approach, where the incidence of the disease among cases were compared with previous exposures among the exposed is compared with the incidence among controls. When the prevalence of the exposure of the non-exposed. The estimation of the exposed and interest among the reference population is low, it non-exposed person-time in the source population is could be difficult to find enough exposed controls to based on drug consumption (see Data analysis).9 estimate it. In the case–population approach, drug A collaborating network, including 12 hospitals cov- consumption data are used, instead of control subjects, ering a population of 2.7 · 106 inhabitants of 15 years to estimate the exposed population to the drugs of of age or older, was set up. Incident cases of ALI were interest.9, 12 The consumption of prescription drugs ascertained from January 1993 to December 1999. was based on the figures for the study area provided Their inclusion in the study was based solely on the clinical inclusion criteria (see Definition of cases), and Table 1. Excluded causes of acute liver injury it was independent from the exposure status. All Serologically proven viral hepatitis patients were interviewed by trained personnel, after AIDS giving informed consent, with a structured question- Intravenous drug addiction naire, covering medical history, clinical course of the Malignant neoplasms present condition, and detailed information on the use Congestive heart failure of medicines in the previous three months. Clinical Acute alcoholic liver disease Shock and laboratory data were also recorded. The methods Sepsis 10 have been described in detail elsewhere. Process causing obstruction of bile flow Cholestatic metabolic diseases Organ transplantation Definition of cases Haemophilia Drug overdosage Acute liver injury was defined as jaundice with a total Mushroom poisoning bilirubin level ‡ 3mg⁄ dL and an acute increase in Chronic liver disease alanine aminotransferase of at least fivefold the upper Autoimmune hepatitis limit of the normal range and ⁄ or an increase in

ª 2007 The Authors, Aliment Pharmacol Ther 25, 1401–1409 Journal compilation ª 2007 Blackwell Publishing Ltd DRUG-INDUCED LIVER DISEASE 1403 by the National Health System, covering the whole considered. Secondly, in order to control for con- population. Intercontinental Marketing Services (IMS, founding by simultaneous exposures to hepatotoxic Fairfield USA) figures were used to estimate the con- drugs, all cases with the concomitant use of drugs sumption of non-prescription medicines. Exposures to with a RR > 25 in the crude analysis were excluded. fixed-dose combinations of two or more drugs were These drugs were: isoniazid, rifampicin, pyrazinamide, considered as single exposures to each component chlorpromazine, droxicam, ticlopidine, ebrotidine, agent. Consumption was transformed into defined amoxicillin with clavulanic acid, erythromycin and daily doses (DDD),13 which enables estimation of the nimesulide. mean number of individuals in the study population treated with the drug of interest.9 For analgesics, for RESULTS which the doses usually taken are much lower than the DDD, the latter were corrected by using the aver- Up to December 31, 1999, the total follow up had been age daily doses which were actually taken by patients 17,616,592 person-years and 126 patients fulfilling in another study in our milieu.14 the inclusion criteria of ALI had been ascertained [68 For each drug, the relative risk (RR) was estimated as (54%) hepatocellular, 35 (27.8%) cholestatic, 23 the ratio between the incidence of ALI among the (18.2%) mixed]. The median age was 61 years (range exposed population, and the incidence of the disease 17–91), and 63 (50%) were female. After 6 months of among the non-exposed to this drug (see Table 2). follow-up, the outcome was unknown in five cases. Because of the rough estimate of the exposed and non- Twenty-four patients presented acute liver failure, of exposed populations, as well as the multiple risks cal- those 19 died (15.7%) and five (4%) underwent liver culated, confidence limits at 99% were used to obtain transplant. an approach to the precision of the estimated risks. A total of 724 exposures to 274 different pharmaco- For certain drugs whose use concentrates in specific logical substances was recorded. A median of 7 (range population groups, the population denominator for the 0–28) different drugs had been taken by the cases dur- estimation of the RR was adjusted to the population at ing the aetiological period. Six patients did not report risk in terms of age (e.g. only those 40 or older for any drug use during the aetiological period. glibenclamide, allopurinol, cardiovascular acetylsali- Table 3 shows the RR estimates and the incidence of cylic acid (ASA), amiodarone, atenolol, enalapril, cap- ALI associated with 38 different drugs that fulfilled topril, or hydrochlorothiazide, or those 60 or older for inclusion criteria, described above. Data are presented ticlopidine or furosemide). Risks associated to herbal by therapeutic groups and the risk magnitude. products could not be estimated because their con- Antituberculous drugs, chlorpromazine and droxi- sumption data were not available. cam were the drugs with the highest risks (RR > 100). Two analyses were performed. First, a crude analysis Table 4 shows the patterns of liver injury associated where any exposure during the aetiological period was with drugs with a RR > 5.

Table 2. Steps in the estimation of the relative risk for speciﬁc drugs, from drug consumption, cases and population data

drug consumption in the study population and period ðin mgÞ Exposed person-years (EP) EP = DDDðinmgÞ365days Non exposed person-years (NEP) NEP = Total person-years – Exposed person-years Exposed cases Incidence in exposed I = E Exposed persons years population (IE) Non exposed cases Incidence in non exposed I = NE Non exposed persons years population (INE) I Relative risk (RR) RR = E INE DDD, deﬁned daily doses is the assumed average maintenance dose per day for a drug used for its main indication in adults.13

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Table 3. Relative risk and incidence rates of acute serious liver disease. Cases with concomitant exposure to drugs with crude RR > 25 are excluded

Incidence rate (n per 100 000 person-years No. of exposed cases of exposure)

Cases without All concomitant Relative cases exposures§§risk 99% CI I 99% CI

Anti-bacterial agents Isoniazid + rifampicin + pyrazinamide 8 8 1299.9 (433–3123) 553.3 (191.8–1244.2) Isoniazid* 4 4 154.3 (29.57–488.7) 63.0 (12.4–188.6) Amoxicillin with clavulanic acid 17 17 66.8 (31.5–128.8) 27.3 (13.7–48.6) Erythromycin 3 3 48.1 (10.6–219.6) 20.5 (2.9–70.8) Amoxicillin without clavulanic acid 3 2 2.3 (0.2–10.3) 1.0 (0.1–4.1) Antipsychotics Chlorpromazine 3 3 613.8 (84.0–2227.1) 261.3 (36.7–902.3) Musculo-skeletal system Droxicam 3 3 142.2 (18.8–557.2) 105.1 (14.8–362.9) Nimesulide 3 3 39.1 (5.3–144.6) 19.1 (2.7–66.1) Allopurinol 4 3 13.9 (1.9–51.4) 7.7 (1.1–26.6) Indomethacin 3 2 13.4 (1.0–60.8) 5.6 (0.4–24.1) Diclofenacà 8 5 7.6 (1.8–22.0) 2.9 (0.7–7.9) Aceclofenac 3 2 7.3 (0.5–33.1) 3.0 (0.2–13.1) Acetylsalicylic acid§ 12 10 5.4 (2.0–12.3) 1.9 (0.7–3.9) Alimentary tract Ebrotidine 4 4 79.9 (14.5–280.5) 35.6 (7.0–106.6) Ranitidine 19 8 13.4 (4.5–32.6) 5.1 (1.8–11.5) Omeprazole 12 5 5.2 (1.2–14.9) 2.1 (0.5–5.6) Metoclopramide 7 4 4.1 (0.8–12.9) 1.7 (0.3–5.0) Cardiovascular system Ticlopidine– 8 7 49.3 (14.6–132.1) 41.8 (13.3–98.8) Amiodarone 3 2 12.3 (0.9–56.6) 7.0 (0.5–30.1) Atenolol 8 5 7.2 (1.7–21.3) 3.9 (1.0–10.6) Captopril 9 3 3.0 (0.4–11.1) 1.7 (0.2–5.8) Furosemide– 6 4 2.8 (0.5–9.4) 2.0 (0.4–6.1) Acetylsalicylic acid ,** 9 5 2.1 (0.5–6.2) 1.0 (0.2–2.7) Hydrochlorothiazide 7 5 1.7 (0.4–4.9) 0.9 (0.2–2.5) Enalapril 6 4 1.5 (0.3–4.7) 0.8 (0.2–2.5) Antiepileptic drugs Phenytoin 3 2 19.2 (1.4–86.9) 8.0 (0.6–34.4) Antidepressants Amitriptyline 3 2 14.2 (1.0–64.2) 5.9 (0.4–25.4) Paroxetine 3 1 3.0 (0.0–21.3) 1.3 (0.0–8.6) Fluoxetine 3 1 1.8 (0.0–12.4) 0.7 (0.0–5.0) Benzodiazepines Potassium clorazepate 5 3 8.3 (1.1–30.3) 3.4 (0.5–11.8) Alprazolam 5 3 4.9 (0.7–18) 2.0 (0.3–7.0) Lorazepam 6 3 3.9 (0.5–14.2) 1.6 (0.2–5.6) Diazepam 4 1 1.7 (0.0–12.2) 0.7 (0.0–5.0) Analgesics Paracetamol 32 17 7.0 (3.3–13.9) 2.4 (1.2–4.2) Metamizoleàà 8 3 3.1 (0.4–11.4) 1.3 (0.2–4.5) Oral antidiabetic agents Glibenclamide 8 5 6.1 (0.9–11.9) 3.3 (0.8–8.9)

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Table 3. (Continued)

Incidence rate (n per 100 000 person-years No. of exposed cases of exposure)

Cases without All concomitant Relative cases exposures§§risk 99% CI I 99% CI

Respiratory system Budesonide 7 4 5.5 (1.0–17.3) 2.2 (0.4–6.6) Salbutamol 8 3 2.8 (0.4–10.3) 1.2 (0.2–4.1)

* Isoniazid for chemoprophylaxis; In patients older than 39; à Topical forms excluded; § Analgesic use: a daily dose of 1000 mg was considered to estimate the exposed population; – In patients older than 59; ** Cardiovascular use; Paracet- amol: a daily dose of 1300 mg was considered to estimate the exposed population; àà Metamizole: a daily dose of 1150 mg was considered to estimate the exposed population; §§ Cases without concomitant exposures to drugs with crude RR > 25.

Acetylsalicylic acid (500–2500 mg daily, median Although the estimates are crude, the RR provides 500 mg) was predominantly hepatocellular pattern. All some estimate of the comparative risk. Our data sug- exposed cases had concomitantly taken various other gest that antibacterial agents, such as isoniazid for drugs or herbs. chemoprophylaxis or associated with rifampicin or The median daily dose of paracetamol taken by the pyrazinamide, amoxicillin with clavulanic acid, and cases was 650 mg (min. 500, max. 3250) and the aver- erythromycin, chlorpromazine and ticlopidine, are the age alcohol consumption was not high (eight out of main contributors to ALI. All of them had been previ- 11 cases), (median intake 13 g ⁄ day, range 0.3–43). ously associated with a risk of ALI, although this had Only three patients were chronic users of paracetamol. been rarely estimated.4–7 In addition, the population- Six additional cases had concomitantly taken other based incidence of ALI is low in our study area, of the drugs or herbal preparations with low hepatotoxic order of 7 (95% CI: 6–8.5) per million inhabitants and potential. Among the 17 cases exposed to paracetamol, year.10 Therefore, moderately high RRs translate into 11 presented with an hepatocellular pattern. the incidence figures of the order of 10–100 cases per Three patients had been exposed to quinolones, but 100 000 person-years of exposure. two had concomitantly used other drugs with a risk Droxicam, the NSAID with the highest risk in our 15 higher than 25 in the crude analysis, thus leaving only study and ebrotidine, an histamine H2-receptor one case (exposed to trovafloxacin). With regard to blocker also associated with a high risk,16 were with- other cardiovascular drugs not shown in Table 3, four drawn from the Spanish market during the study per- patients had been exposed to statins, but only one on iod. The use of nimesulide has been restricted by the pravastatin had not taken another high risk drug con- EMEA because of its potential hepatotoxicity.17 comitantly. Ten patients had been exposed to natural Our research confirms that antituberculous drugs products or medicinal herbs, six of whom were tend to cause hepatocellular damage.18–20 It also unknown. confirms the risk of liver damage associated with Detailed information on the process of case ascer- erythromycin.18, 19 The combination of amoxicillin tainment, primary and secondary exclusions, inci- and clavulanic acid was strongly associated with pre- dence, mortality, case-fatality rate, exposures to drugs dominantly cholestatic or mixed pattern,18 as previ- and herbs are available at http://www.icf.uab.es/asld. ously described.5, 21 The risk of cholestatic hepatitis associated with chlorpromazine is well known,18 and this was the pre- DISCUSSION vailing pattern among the exposed cases in our study. This study provides the risk estimates of acute serious Its incidence rate was similar to that observed in other liver injury for various commonly used drugs. studies.4, 5

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Exposed cases Table 4. Patterns of liver injury associated with drugs Total Cholestatic Hepatocellular Mixed with relative risk >5.

Anti-bacterial agents Clavulanic acid 17 9 3 5 Isoniazid + rifampicin + pyrazinamide 8 1 7 – Isoniazid* 4 – 3 1 Erythromycin 3 – 1 2 Analgesics Paracetamol 17 4 11 2 Musculo-skeletal system Acetylsalicylic acid 10 2 7 1 Diclofenacà 51 4 – Allopurinol 3 2 – 1 Droxicam 3 1 1 1 Nimesulide 3 – 3 – Aceclofenac 2 1 – 1 Indomethacin 2 – 2 – Alimentary tract and metabolism Ranitidine 8 4 3 1 Glibenclamide 5 3 2 – Omeprazole 5 1 2 2 Ebrotidine 4 – 4 – Metoclopramide 4 1 3 – Cardiovascular system Ticlopidine 7 7 – – Atenolol 5 1 2 2 Amiodarone 2 1 1 – Respiratory system Budesonide 4 2 1 1 Antipsychotics Chlorpromazine 3 2 1 – Benzodiazepines Potassium clorazepate 3 1 2 – Antidepressants Amitriptyline 2 – 1 1 Antiepileptics Phenytoin 2 2 – –

* Isoniazid for chemoprophylaxis; Acetylsalicylic acid at analgesic doses; à Topical forms excluded.

The hepatotoxic potential of ticlopidine is well related to diclofenac) may be associated with a established. In our study, the risk associated with its moderate risk of ALI. Our results on diclofenac are case was high, and the predominant pattern was chol- consistent with those of other epidemiological stud- estatic. In premarketing clinical trials, an incidence of ies with wider inclusion criteria, where a moderate 0.4–4% of transient serum liver enzyme increases and risk of ALI has been found. 5, 7 A few anecdotal hepatitis was reported,22 which compared with 42 cases have also been reported in relation with cases per 100 000 exposed person-years with our aceclofenac.23, 24 stricter criteria. The risk associated with ASA was higher with anal- Our results suggest that indomethacin, diclofenac, gesic doses than with the cardiovascular low doses, and probably aceclofenac (which is structurally although both estimates were relatively low. These

ª 2007 The Authors, Aliment Pharmacol Ther 25, 1401–1409 Journal compilation ª 2007 Blackwell Publishing Ltd DRUG-INDUCED LIVER DISEASE 1407 data should be considered with caution, as all patients risk of acute liver disease compared with those not had also taken other drugs or herbs with some poten- taking these drugs.34 tial for liver injury. Although the liver toxicity of ASA Our results show an unexpected association with in patients with connective tissue diseases on high inhaled budesonide. Only one case of liver injury doses is known since old times,18, 19 the risk of inter- associated to this drug had been reported until mediate doses has not been appropriately evaluated in now,35 and no association was found in a recent studies in large administrative databases, because study.5 This association should be confirmed by exposure to over-the-counter drugs is usually not further studies. recorded. Although ACE inhibitors have been related to liver We found a moderate risk of ALI associated with injury,18 our results confirm those of a previous paracetamol at usual analgesic doses and a recent study.5 Weak associations were seen with exposure to study pointed it out.25 Low-dose paracetamol other cardiovascular drugs, such as diuretics (furosem- (£4g⁄ day) liver toxicity is believed to be rare, as there ide and hydrochlorothiazide), or low-dose ASA. are very few fully documented cases.26 Most cases had The association found with SSRIs is weak. Drug taken high drug doses.27 The toxic safety threshold of monitoring agencies have received a number of reports paracetamol seems to be influenced by a large number of acute hepatitis related to SSRIs,36 but our results of genetic and environmental factors,28 including and those of another study do not confirm this associa- inadequate dietary protein and food intake with the tion.5 depletion of glutathione stores, the induction of cyto- Benzodiazepines are considered a rare cause of liver chrome P450 by alcohol, and fasting seem to increase disease.5 Our results suggest that the hepatotoxic the risk.27 Acute poisoning by paracetamol is an infre- potential is low, except for potassium clorazepate that quent cause of hepatic liver failure in Spain, in con- is associated with a moderate risk. trast to other countries (UK).29 Our study has several strengths. First, case definition Our results also suggest that ranitidine and omep- depended on strict clinical criteria rather than on razole may be associated with a higher risk of ALI exposure to a particular drug, and systematic compared with that published in some previous stud- ascertainment of all patients fulfilling the study cri- ies.5, 30 Metoclopramide, which had been incriminated teria was done within the study defined population. In in a few cases of hepatitis in patients on antineoplastic order to avoid selection bias, only serious forms of drugs18, 19 and with a moderate risk in an epidemio- ALI, usually with jaundice, were included. It is unli- logical study, was also associated with a low risk of kely that patients with particularly serious forms of ALI.5 We cannot exclude that residual confounding by liver injury, such as those defined in this study do not indication could explain these moderate associations, come to the attention of hospital care. Secondly, as these drugs may have been taken for unspecific researchers ascertained and validated all the cases symptoms of liver disease. blindly with respect to the exposure status. Thirdly, Atenolol was also associated with a moderate risk of details on the earlier use of medicines, including over ALI. It has seldom been reported as a cause of the counter drugs and herbs, were carefully recorded ALI,31, 32 and, in a recent epidemiological study, no by inquiring patients with a detailed structured ques- association of beta-blockers with ALI was seen.5 tionnaire about the symptoms and the specific indica- Labetalol is the only beta-adrenoceptor blocker that tions that covered the use of drugs most frequently has been related to hepatic injury in several case associated with liver injury, and by showing them pic- reports. 19, 33 tures of the major pharmaceuticals of interest. Four- Various drugs were found to be associated with a thly, risks were estimated by adjusting by the moderate risk. Some of them, such as phenytoin,33 concomitant use of other potential hepatotoxic amitriptyline,5, 18, 19 amiodarone,18, 19 or allopurinol,18 drugs. Additionally, the risk ratios were adjusted for are well known hepatotoxic drugs. Unfortunately, the differential use of various drugs indicated for their risk estimates are based on very few exposed diseases concentrating on specific age groups. The cases. case–population approach for risk estimation when the We also found a moderate risk of ALI associated prevalence of use of the drugs of interest among those with glibenclamide. In another study, patients with not affected is low, has been shown for a long period diabetes taking antidiabetic drugs presented a higher in pharmacovigilance studies.9, 37–39 Fifthly, all drugs

ª 2007 The Authors, Aliment Pharmacol Ther 25, 1401–1409 Journal compilation ª 2007 Blackwell Publishing Ltd 1408 M. SABATE´ et al. with high risk are among those described as hepato- confirm the hepatotoxicity of several commonly used toxic and that gives consistency to our results and medicines (e.g. antituberculous agents, chlorproma- sixthly, we have estimated the risks of drugs previ- zine, and to a lesser extent ticlopidine, amoxicillin ously not related with ALI, as we took into account with clavulanic acid, erithromycin, nimesulide, allo- the frequency of exposure to drugs, independently of purinol, phenytoin, and amiodarone), they suggest a their known hepatotoxic potential. moderate risk associated to glibenclamide, omepraz- However, some concerns may be expressed. First, ole, metoclopramide, and paracetamol at therapeutic drug use in the community is expressed as person- doses, and, last but not the least, they confirm the time exposed population to an established represen- safety with regard to the lives of a vast number of tative dose (i.e. we have assumed that the drug risk medicines. This risk magnitude for each drug should is not associated with the exposure length or the be compared with its potential therapeutic benefit in dose of the drug). Thus, the risk estimates associated each indication, taking also into account the with several drugs in the same group may vary availability of therapeutic choices. However, according to their course lengths and ⁄ or doses (e.g. unexpected associations have to be confirmed by analgesics or NSAIDs). While risks have been estima- further studies. ted by restricting on the concomitant use of drugs Recent tragedies in drug safety, such as those of known to be associated with liver injury, we cannot hormonal replacement therapy and the coxibs, indicate exclude that other potential hepatotoxic drugs not that the conventional pharmacovigilance systems identified as such so far may have confounded our based upon voluntary reporting of suspicious of results. Although several risk estimates show wide adverse effects are inadequate to follow up the use confidence intervals, their magnitude suggests that and the safety of new medicines. Collaborating net- they reflect a true causal relationship with ALI. works should be encouraged and supported by the reg- Unfortunately, we cannot report on the risks associa- ulatory authorities and the health care organizations ted with immunosupressant drugs, cytostatics and, where the use of medicines takes place. These net- antirretrovirals, because patients with conditions works should be part of a permanent observatory to treated with those drugs were excluded in order to contribute to a safer use of medicines. avoid confounding by indication. Similarly, we cannot report on the risk of liver damage in patients ACKNOWLEDGEMENTS with chronic liver disease. On the other hand, the risk associated to statins, quinolones, new macrolides Consumption data from IMS were provided by Pharma or oral contraceptives could not be estimated due to and Cia. very few exposed cases. Declaration of personal interests: None. Our results provide a spot picture of drug-induced Declaration of funding interests: The study was sup- liver injury in an epidemiological and public health ported by grants from: CIRIT (Comisionat per a Uni- perspective in our milieu, where the pattern of versitats I Recerca, generalitat de Catalunya) Accions medicine consumption is not substantially different Mobilitzadores (1995XT 00030) and Boehringer- from that in other industrialized countries. They Ingelheim, Barcelona.

REFERENCES on Adverse Drug Reactions between injury using the General Practice 1978 and 1987. J Intern Med 1992; Research Data Base in the United 1 Lasser KE, Allen PD, Woolhandler SJ, 232: 133–8. Kingdom. Pharmacoepidemiology 1997; Himmelstein DU, Wolfe SM, Bor DH. 3 Garcıá Rodrı´guez LA, Pe´rez Gutthann S, 17: 721–8. Timing of new black box warnings and Walker AM. The role of non-steroidal 5 de Abajo FJ, Montero D, Madurga M, withdrawals for prescription medica- anti-inflammatory drugs in acute liver Garcıá Rodrı´guez LA. Acute and tions. JAMA 2002; 287: 2215–20. injury. BMJ 1992; 305: 865–8. clinically relevant drug-induced liver 2 Friis H, Andreasen PB. Drug-induced 4 Garcıá Rodrı´guez LA, Ruigomez A, injury: a population based case–control hepatic injury: an analysis of 1100 Jick H. A review of epidemiologic study. Br J Clin Pharmacol 2004; 58: cases reported to the Danish Committee research on drug-induced acute liver 71–80.

ª 2007 The Authors, Aliment Pharmacol Ther 25, 1401–1409 Journal compilation ª 2007 Blackwell Publishing Ltd DRUG-INDUCED LIVER DISEASE 1409

6 Carson JL, Duff A, Strom BL. Drug- 17 The European Agency for the Evalua- 29 Mas A, Escorsell MA, Fernańdez J. Insu- induced acute liver disease. Pharmaco- tion of Medicinal Products. Committee ficiencia hepa´tica aguda Grave. In: Net epidemiol Drug Saf 1993; 2: S19–23. for propietary medicinal products A, Betbese´ AJ, eds. Update en Medicina 7Pe´rez Gutthann S, Garcıá Rodrı´guez LA. (CPMP) opinion following an article 31 Intensiva, Barcelona: Ars Medica, The increased risk of hospitalizations referral. 2004. CPMP ⁄ 1724 ⁄ 04. (http:// 2005:343–56 for acute liver injury in a population www.emea.eu.int/pdfs/human/referral/ 30 Garcıá Rodrı´guez LA, Wallander MA, with exposure to multiple drugs. Epi- nimesulide/172404en.pdf). Stricker BHCh. The risk of acute liver demiology 1993; 4: 496–501. 18 Stricker BHCh. Drug-induced hepatic injury associated with cimetidine and 8 Andrade RJ, Lucena MI, Fernandez MC, injury, 2nd edn. Amsterdam: Elsevier, other acid-suppressing anti-ulcer drugs. et al. Spanish Group for the Study of 1992. Br J Clin Pharmacol 1997; 43: 183–8. Drug-Induced Liver Disease. Drug- 19 Zimmerman HJ. Hepatotoxicity: the 31 Schwartz MS, Frank MS, Yanoff A, induced liver injury: an analysis of 461 adverse effects of drugs and other Morecki R. Atenolol-associated choles- incidences submitted to the spanish chemicals on the liver, 2nd edn. Phil- tasis. Am J Gastroenterol 1989; 84: registry over a 10-year period. Gastro- adelphia: Lippincot Williams & Wilkins, 1084–6. enterology 2005; 129: 512–21. 1999. 32 Yosuf SW, Mishra RM. Hepatic dysfunc- 9 Capella` D, Pedro´s C, Vidal X, Laporte 20 Nolan CM, Goldberg SV, Buskin SE. tion associated with atenolol. Lancet JR. Case–population studies in pharma- Hepatotoxicity associated with isoniazid 1995; 346: 192. coepidemiology. Drug Saf 2002; 25: preventive therapy. JAMA 1999; 281: 33 Chitturi S, George J. Hepatotoxicity of 7–19. 1014–8. commonly used drugs: nonsteroidal 10 Ibań˜ez L, Pe´rez E, Vidal X, Laporte JR, 21 Garcıá Rodrı´guez LA, Stricker BH, anti-inflammatory drugs, antihyperten- GEMHAB. Prospective surveillance of Zimmerman HJ. Risk of acute liver sives, antidiabetic agents, anticonvul- acute serious liver disease unrelated to injury associated with the combination sants, lipid-lowering agents, infectious, obstructive, or metabolic dis- of amoxicillin and clavulanic acid. Arch psychotropic drugs. Semin Liver Dis eases: epidemiological and clinical fea- Intern Med 1996; 156: 1327–32. 2002; 22: 169–83. tures, and exposure to drugs. J Hepatol 22 Pizarro AE, Andrade RJ, Garcıá-Corte´s 34 Huerta C, Zhao SZ, Garcıá Rodrı´guez 2002; 37: 592–600. M, Lucena MI, Pe´rez-Moreno JM, LA. Risk of acute liver injury in patients 11 Benichou C. Criteria of drug-induced Puertas M. Acute hepatitis due to ticl- with diabetes. Pharmacotherapy 2002; liver disorders. Report of an interna- opidine. A report of 12 cases and review 22: 1091–6. tional consensus meeting. J Hepatol of the literature. Rev Neurol 2001; 33: 35 Sagir A, Wettsein M, Oette M, Erhardt 1990; 11: 272–6. 1014–20. A, Haüssinger D. Budesonide-induced 12 Ibań˜ez L, Ballarıń E, Vidal X, Laporte 23 Zaragoza A, Moreno V, Catala´ E. acute hepatitis in an HIV-positive J-R. Agranulocytosis associated with NSAID-induced hepatotoxicity: aceclof- patient with ritonavir as co-medication. calcium dobesilate. Clinical course and enac and diclofenac. Rev Esp Enferm AIDS 2002; 16: 1191–2. risk estimation with de case–control and Dig 1995; 87: 472–5. 36 Capella` D, Bruguera M, Figueras A, the case–population approaches. Eur 24 Pe´rez JM, Puertas M, Fernańdez A, Gon- Laporte JR. Fluoxetine-induced hepati- J Clin Pharmacol 2000; 56: 763–7. za´lez MA. Toxic hepatitis caused by tis: why is postmarketing surveillance 13 Wessling A, Boe¨thius G. Measurement aceclofenac. Rev Esp Enferm Dig 1996; needed? Eur J Clin Pharmacol 1999; 55: of drug use in a defined population. 88: 815–6. 545–6. Evaluation of the defined daily dose 25 Watkins PB, Kaplowitz N, Slattery JT, 37 Inman WHW. Study of fatal bone mar- (DDD) methodology. Eur J Clin Pharma- et al. Aminotransferase elevations in row depression with special reference to col 1990; 39: 207–10. healthy adults receiving 4 grams of phenylbutazone and oxyphenbutazone. 14 Laporte JR, Ibań˜ez L, Vidal X, Vendrell acetaminophen daily. JAMA 2006; 296: BMJ 1977; 1: 1500–5. L, Leone R. Upper gastrointestinal bleed- 87–93. 38 Keisu M, Ekman E, Wiholm B-E. Compar- ing associated with the use of NSAIDs: 26 Graham GG, Scott KF, Day RO. Tolerab- ing risk estimates of sulphonamide- newer versus older agents. Drug Saf ility of paracetamol. Drug Saf 2005; 28: induced agranulocytosis from the 2004; 27: 411–20. 227–40. Swedish Drug Monitoring System and a 15 Anonymous. Droxicam and hepatotox- 27 Prescott LF. Therapeutic misadventure case–control study. Eur J Clin Pharmacol icity-suspension of marketing authorisa- with paracetamol: fact or fiction. Am 1992; 43: 211–4. tions recommended. Who Pharmaceut J Ther 2000; 7: 99–114. 39 Cheeta S, Schifano F, Oyefeso A, Webb Newsletter 1995; 2:1. 28 Lee W. Acetaminophen and the U.S. L, Ghodse AH. Antidepressants-related 16 Anonymous. Withdrawal of medicinal Acute Liver Failure Study Group: lower- deaths and antidepressant prescriptions products containing ebrotidine: liver ing the risks of hepatic failure Hepatolo- in England and Wales, 1998–2000. Br toxicity. WHO Inform Exchange Syst gy 2004; 40: 6–9. J Psychiatry 2004; 184: 41–7. 1998; 72:1.

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