Relationship Between Daily Dose of Oral Medications
`and Idiosyncratic Drug-Induced Liver Injury: Search
`for Signals
`
`Craig Lammert,1 Stefan Einarsson,2 Chandan Saha,3 Anna Niklasson,2 Einar Bjornsson,2 and Naga Chalasani3
`
`Idiosyncratic drug-induced liver injury (DILI) is traditionally thought not to be dose-related. How-
`ever, it has been pointed out that most medicines that were withdrawn from marketing or received a
`black-box warning because of hepatotoxicity were prescribed at daily doses greater than 50 mg/day.
`To examine the relationship between daily dose of medications and idiosyncratic DILI, we conducted
`a study with two aims. First, using two pharmaceutical databases, we examined the relationship
`between daily dose of commonly prescribed medicines in the United States and reported frequency of
`their selected hepatic adverse events. Second, we examined serious DILI cases reported to the Swedish
`AdverseDrugReactionsAdvisoryCommittee(1970-2004)foranysignalssupportingtherelationship
`between daily dose and idiosyncratic DILI. Medications were categorized into <10 mg/day, 11-49
`mg/day, and >50 mg/day groups. Among US prescription medicines, a statistically significant rela-
`tionship was observed between daily dose of oral medicines and reports of liver failure (P ⴝ 0.009),
`liver transplantation (P< 0.001), and death caused by DILI (P ⴝ 0.004) but not alanine aminotrans-
`ferase (ALT) > 3 ⴛ upper limit of normal (Pⴝ 0.10) or jaundice (Pⴝ 0.16). Of 598 eligible Swedish
`DILI cases, 9% belonged to the <10 mg/day group, 14.2% to the 11-49 mg/day group, and 77% of
`cases were caused by medications given at dose >50 mg/day. A statistically significant relationship was
`noted between daily dose and poor outcome (death or liver transplantation) of Swedish DILI cases
`(2%, 9.4%, and 13.2% in <10, 11-49, and >50 mg/day groups, respectively, P ⴝ 0.03). Conclusion:
`These data suggest a relationship between daily doses of oral prescription medications and idiosyn-
`cratic DILI. More studies are needed to validate these observations and to explore their implications.
`(HEPATOLOGY 2008;47:2003-2009.)
`
`See Editorial on Page 1813
`
`Abbreviations: ALT, alanine aminotransferase; APAP, acetaminophen; DILI,
`drug-induced liver injury.
`From the 1Department of Medicine, Emory University School of Medicine, At-
`lanta, GA; 2Department of Internal Medicine, Sahlgrenska University Hospital,
`Gothenburg, Sweden; and 3Department of Medicine, Indiana University School of
`Medicine, Indianapolis, IN.
`Received November 12, 2007; accepted January 30, 2008.
`Supported in part by National Institutes of Health grant K 24 DK 072101
`(N.C.).
`Address reprint requests to: Naga Chalasani, M.D., Associate Professor of Med-
`icine, Indiana University School of Medicine, RG 4100, 1050 Wishard Boulevard,
`Indianapolis, IN 46202. E-mail: nchalasa&iupui.edu; fax: 317-630-6815.
`Copyright © 2008 by the American Association for the Study of Liver Diseases.
`Published online in Wiley InterScience (www.interscience.wiley.com).
`DOI 10.1002/hep.22272
`Potential conflict of interest: Dr. Chalasani is a consultant for Takeda, Pfizer, Advanced
`Life Sciences, Atherogenics, Metabasis, and Lilly. He also received grants from Sanofi-Roche.
`Dr. Bjornsson is a consultant for AstraZeneca and Astellas.
`
`Idiosyncratic drug-induced liver injury (DILI) is rare,
`
`but when it occurs it may have serious consequences.1
`It is one of the most frequent causes of acute liver
`failure in the United States1,2 and in fact is one of the most
`common reasons for not receiving approval or for with-
`drawal from marketing by the United States Food and
`Drug Administration.3 The pathogenesis of idiosyncratic
`DILI is not well understood but is generally thought to be
`unpredictable and not dose-dependent. However, it has
`been pointed out that most drugs that either have been
`withdrawn from the market or have received a black box
`warning due to hepatotoxicity were prescribed at daily
`doses greater than 50 mg, suggesting some dose relation-
`ship4 (Table 1). There is some relationship between daily
`dose of a medication (for example, statins, bosentan) and
`the reported frequency of elevated aminotransferases, sug-
`gesting that in some instances DILI may be dose-depen-
`dent.5,6 Anecdotally, we have observed many instances in
`which individuals developed clear-cut hepatotoxicity on
`increasing the dose of a medication that they have re-
`
`2003
`
`AstraZeneca Exhibit 2164
`Mylan v. AstraZeneca
`IPR2015-01340
`
`Page 1 of 7
`
`

`
`2004
`
`LAMMERT ET AL.
`
`HEPATOLOGY, June 2008
`
`Table 1. Daily Doses of Medications That Either Have Been
`Withdrawn from the United States Market or Have Received
`Hepatotoxicity Warning by the FDA
`
`Compound
`
`Iproniazid
`Ticrynafen
`Benoxaprofen
`Bromlenac
`Troglitazone
`Ximelagalran*
`
`Withdrawn from Marketing
`Year
`
`1956
`1979
`1982
`1998
`2000
`2006
`
`Daily Dosage
`
`100–250 mg
`250–500 mg
`600 mg
`75–100 mg
`400–600 mg
`48–72 mg
`
`Hepatotoxicity Warnings
`
`Strong Warning of Serious
`Hepatotoxicity
`
`Moderate Warning of Serious
`Hepatotoxicity
`
`Compound
`
`Daily Dosage
`
`Compound
`
`Daily Dosage
`
`Zileuton
`Tacrine
`Labetalol
`Diclofenac
`Dantrolene
`
`1600–2400 mg
`40–160 mg
`200–400 mg
`75–200 mg
`25–400 mg
`
`Valproic acid
`Ketoconazole
`Nicotinic acid
`Rifampin
`Chlorzoxazone
`Isoniazid
`Dantrolene
`Nefazadone
`Telethromycin
`Nevirapine
`Atomoxetine
`Infliximab
`
`250–1250 mg
`200–800 mg
`100–4500 mg
`300–1200 mg
`750–3000 mg
`300 mg
`25–400 mg
`200–600 mg
`800 mg
`200–400 mg
`40–100 mg
`5 mg/kg
`
`Assigned as Second-line Agents Because of Hepatotoxicity
`
`Compound
`
`Pemoline
`Tolcapone
`Trovafloxacin
`Febamate
`
`Daily Dosage
`
`mean 56-75 mg, max 112.5 mg
`300 mg
`50–200 mg
`1200–3600 mg
`
`NOTE. It is striking that almost all these compounds were given at doses greater
`than 50 mg per day.
`*Was not approved by FDA for marketing in the USA and was withdrawn from
`worldwide marketing.
`
`ceived at stable doses for a lengthy period. For example, a
`middle-aged woman without known underlying liver dis-
`ease or alcoholism developed pronounced hepatotoxicity
`caused by duloxetine very soon after increasing its dose to
`60 mg/day, although she received 30 mg/day duloxetine
`for many weeks with no complications (unpublished
`data). These observations raise the possibility that some
`relationship may exist between daily dose of a medication
`and its propensity to exhibit hepatotoxicity. However,
`this has not been previously studied in a formal fashion.
`To explore for an association between daily dose of
`medications and idiosyncratic DILI, we conducted a
`study with two specific aims. First, using two comprehen-
`sive pharmaceutical databases, we examined the relation-
`ship between daily dose of oral medications that are
`commonly prescribed in the United States and reported
`frequency of their hepatic adverse events. Second, we ex-
`
`amined the daily doses of oral medications that have been
`implicated in the reports of suspected hepatic adverse
`drug reactions submitted to the Swedish Adverse Drug
`Reactions Advisory Committee during the period 1970 to
`2004.
`
`Materials and Methods
`
`First Aim. We used a publicly available pharmacy da-
`tabase (www.drugtopics.com) to extract the names of the
`top 200 brand and top 200 generic medications by pre-
`scription volume in the United States during the year
`2005.7,8 Duplicate compounds were reduced to a single
`entry, and nonoral medications were removed. List com-
`pilation yielded 230 medications available for further
`consideration. These compounds were further catego-
`rized into dosage groups of 10 mg or less, 11 to 49 mg,
`and 50 mg or greater based on daily recommended doses
`(Table 2). The compounds with broad ranges of recom-
`mended daily dose were placed within dosage groups
`based on the average of maximum and minimum recom-
`mended daily dose. For example, atorvastatin, with a daily
`recommended dose ranging between 10 and 80 mg (av-
`erage, 45 mg) was placed in the 10-mg to 50-mg group.
`We subsequently reviewed each of these medications to
`assess whether they were ever reported to have caused
`selected hepatic adverse events, using the Thompson’s
`Micromedex Drugdex System. Drugdex is one of the
`most comprehensive pharmacy databases, consisting of
`package insert data and published literature.9 Hepatic ad-
`verse events selected for this specific aim were alanine
`aminotransferase (ALT) greater than 3 times the upper
`limit of normal, cholestatic jaundice, liver failure, liver
`transplantation, and death caused by hepatic injury. To
`ensure completeness, each listed compound was cross-
`checked in the PubMed, Adverse Event Reporting System
`database, and the Physicians’ Desk Reference.10-12 For each
`listed compound, we extracted whether these selected he-
`patic adverse events were reported rather than the number
`of events reported.
`Second Aim. All reports of suspected drug-induced
`liver injury received by the Swedish Adverse Drug Advi-
`sory Committee since 1970 have been computerized. The
`reporting of fatal, otherwise serious, and new reactions
`has been compulsory since 1975. In a previous paper, the
`number and nature of suspected adverse drug-induced
`liver disease associated with fatalities or leading to liver
`transplantation between 1966 and 2002 were reported
`(Swedish DILI death/transplant cases).13 In a subsequent
`paper, all cases of suspected DILI with concomitant jaun-
`dice reported between 1970 and 2004 were reviewed for
`assessing outcome and prognostic markers of severe DILI
`
`Page 2 of 7
`
`

`
`HEPATOLOGY, Vol. 47, No. 6, 2008
`
`LAMMERT ET AL.
`
`2005
`
`Table 2. Most Commonly Prescribed Medicines in the United
`States Categorized into Three Dose Groups
`<10 mg/day
`>50 mg/day
`(n ⴝ 54)
`(n ⴝ 93)
`
`11–49 mg/day
`(n ⴝ 83)
`
`Actonel
`Alprazolain
`Altace
`Amaryl
`Aricept
`Arimidex
`Avandia
`Benazepril
`Benztropine
`Bisoprolol/HCTZ
`Bumetanide
`Beoestin
`Cialis
`Clannex
`Clonazepam
`Colchicine
`Coumadin
`Detrol LA
`Diazepam
`Digitek
`Ditropan
`Doxazosin
`EE/ethynodiol di
`Felodipine ER
`Flomax
`Fosinopril sod
`Glipizide XL
`Glyburide
`Hyoscyamine
`Indapamide
`Levonorgestrel
`Lorazepam
`Lotrel
`Lowogestrel
`Lunesta
`Mavik
`Metolazone
`Mirapex
`Mobic
`Namenda
`Norethindrone/ee
`Norgestimate/ee
`Norvasc
`Prednisone oral
`Premarin
`Prempro
`Proscar
`Risperdal
`Synthroid
`Temazepam
`Terazosin
`
`Tizanidine HCl
`Yasmin 28
`Zyrtec
`
`Ahilify
`Accupril
`Aciphex
`Actos
`Adderall XR
`Ambien
`Atacand
`Baclofen
`Benicar
`Benicar HCT
`Bextra
`Buspirone HCl
`Captopril
`Citalopram HBR
`Clorazepate dipot
`Concerta
`Coreg
`Cozaar
`Crestor
`Cymbalta
`Diovan
`Diphenhydramine tabs
`Diphenoxylate w/Atro
`Doxepin
`Effexor XR
`Farnotidine
`Flexeril
`Fluoxetine
`Fosamax
`Furoscmide oral
`Geodon oral
`Hydralazine
`Hydrochlorothiazide
`Hydroxyzine
`Imitrex Oral
`Indomethacin
`Isosorbide mononitrate
`Lescol
`Levitra
`Lexapro
`Lipitor
`Lisinopril
`Lisinopril/HCTZ
`Lovastatin
`Meclizine HCl
`Methadose
`methlyprednis
`Metoclopramide
`Metoprolol tartrate
`Micardis
`Mirtazapine
`
`Nadolol
`Nexium
`Nifedipine ER
`Omeprazole
`Oxycodone
`Oxycontin
`Paxil CR
`Phentermine
`Piroxicam
`Pravachol
`prednisolone
`
`Acyclovir
`Allegra-D 12 hour
`Allopurinol
`Amiodarone
`Amitriptyline
`Amoxicillin
`Amoxicillin/clavulanate
`Aspirin, Enteric-Coat
`Atenolol
`Atenolol chlorthal
`Atomoxctine hyrdochloride
`Azithromycin
`Benzonatate
`Bupropion hydrochloride
`Carhamazepine
`Carbidopa/levodopa
`Carisoprodol
`Cefdinir
`cefprozil
`Celuroxime Axctil
`Celecoxib
`Cephalexin
`Cimetidine
`Ciprofloxacin HCl
`Clarithromycin
`Clopidrogel hydrogen sulfate
`Diclofenac Sodium
`Diclofenac sodium/misoprostol
`Dicyclomine HCl
`Diltiazem hydrochloride
`Docusate sodium
`Doxycycline
`Etodolac
`Fenofibrate
`Fexofenadine hydrochloride
`Fluconazole
`Gabapentin
`Gemfibrozil
`Glyburide/metformin HCl
`Hydrochlorothiazide/valsartan
`Hydrocholorthiazide/irbesartan
`Hydroxychloroquine
`Hydroxyzine Pamoate
`Ibuprofen
`Imipramine HCl
`Irbesartan
`Labetalol
`Lamotrigine
`Levetiracetam
`Levofloxacin
`Lithium Carbonate
`Losartan potassium-
`hydrochlorothiazide
`Mesalamine
`Metaxalone
`Metformin
`Metformin/rosiglitazone
`Methocarbamol
`Metronidazole Tabs
`Minocycline
`Modafinil
`Moxifloxacin hydrochloride
`Mytussin AC
`
`Table 2. (Continued)
`
`<10 mg/day
`(n ⴝ 54)
`
`11–49 mg/day
`(n ⴝ 83)
`
`>50 mg/day
`(n ⴝ 93)
`
`Prevacid
`Prochlorperaz mal
`Promethazine tabs
`Protonix
`Relpax
`Ritalin-LA
`Singulair
`Spironolactone
`Tamoxifen
`Thyroid, Armour
`Timolol Maleate GFS
`Tuprol XL
`Tramadol
`Triamterene w/HCTZ
`Tussionex
`Viagra
`Vytorin
`Zelnorm
`Zetia
`Zocor
`Zyprexa
`
`Nabumetone
`Naproxen
`niacin
`Nurtriptyline
`Nitrofurantoin
`Oseltamivir phosphate
`oxcarbazepine
`Penicillin VK
`Pentoxifylline
`Phenazopyridine HCl
`Phenobarbital
`Phenytoin
`Progesterone
`Propranolol hydrochloride
`Quetiapine furnarate
`Quinine sulfate
`Raloxifene hydrochloride
`Ranitidine hydrochloride
`Scrtraline
`Sotalol
`Telithromycin
`Terbinafine hydrochloride
`Tetracycline
`Theophylline SR
`Topiramate
`Trandolapril/verapamil
`Trazodone HCl
`Trimethoprim/Sulfa
`Valacyclovir hydrochloride
`Valproic Acid (divalproex
`sodium)
`Verapamil SR
`
`(Swedish DILI jaundice cases).14 Cases contained within
`these two data sets were retrieved, and duplicate entries
`were excluded from further consideration. The causality
`was rigorously assessed according to the International
`Consensus Criteria,15-17 and all cases had least “possible”
`causality relationship. Apart from the daily dose of the
`implicated medication, the following information was re-
`trieved from the reports: drug(s) suspected, results of peak
`aspartate aminotransferase, ALT, alkaline phosphatase,
`and bilirubin values, and outcome (recovery, death, or
`liver transplantation). Cases with more than one drug
`suspected to have caused DILI and acetaminophen alone
`or in combination with other drugs were excluded. Only
`oral medications were included in the analysis. The im-
`plicated medications were categorized into 10 mg or less,
`11 to 49 mg, and 50 mg or greater based on the daily
`dosage. The objectives were to examine how many Swed-
`ish DILI cases belonged to each of these dosage groups
`and to explore the relationship between daily dose and
`outcome of Swedish DILI cases.
`For aim 2, as a supplement to the Swedish DILI data,
`we reanalyzed the paper published by Russo et al.,18 which
`
`Page 3 of 7
`
`

`
`2006
`
`LAMMERT ET AL.
`
`HEPATOLOGY, June 2008
`
`Table 3. Association Between Daily Doses of Oral Prescription Medications and Hepatic Adverse Events
`<10 mg
`>50 mg
`(n ⴝ 54)
`(n ⴝ 93)
`
`10–50 mg
`(n ⴝ 83)
`
`Number of Compounds
`Reported To Have Caused
`
`ALT ⬎ 3 ⫻ ULN (n, %)
`Jaundice (n, %)
`Liver Failure (n, %)
`Death (n, %)
`Transplant (n, %)
`Prescriptions (median in 2005)
`
`10 (19)
`18 (33)
`9 (17)
`6 (11)
`0 (0)
`4,746,500
`
`22 (27)
`33 (40)
`10 (12)
`9 (11)
`2 (2)
`4,938,000
`
`29 (31)
`42 (45)
`30 (32)
`26 (28)
`12 (13)
`3,733,000
`
`P-Value
`
`0.10
`0.16
`0.009
`0.004
`⬍0.001
`0.3
`
`For example, 19% of compounds belonging to the ⬍10 mg group have been reported to cause ALT ⬎ 3 ULN, whereas 27% of compounds belonging to the 10 –50
`mg group and 31% of compounds belonging to the ⬎50 mg group (P-value ⫽ 0.10). Another example: 32% of compounds belonging to the ⬎50 mg group have
`been reported to cause liver failure in comparison with 17% in the ⬍10 mg group and 12% in the 10 –50 mg groups (P ⬍ 0.01).
`
`consisted of 270 DILI cases that required liver transplan-
`tation in the United States between 1990 and 2002.18 Of
`these 270 cases, 133 were acetaminophen (APAP) related,
`and 137 were non–APAP related. We examined how
`many of these non-APAP cases belonged to 10 mg/day or
`less, 11 to 49 mg/day, and 50 mg/day or greater groups.
`Statistics. For aim 1, proportions were used to de-
`scribe the clinical dichotomous outcomes. The Kruskal-
`Wallis test compared the distribution of the number of
`times a compound was prescribed in 2005 among the
`three groups of compounds. The Cochran-Armitage
`trend test was applied for association between clinical out-
`comes and compounds. The overall logistic regression
`model linked the odds of ever reporting an incidence of
`clinical outcome to the covariate, three groups of com-
`pounds. For the validity of the model fitting for the trans-
`plant outcome, we used two groups of compounds, less
`than 50 mg versus 50 mg or greater, because none of the
`compounds in the less than 10 mg group had undergone
`transplantation. Estimated odds ratios and 95% confi-
`dence intervals were reported. For aim 2, descriptive sta-
`tistics and Fisher’s exact test were used to analyze the data.
`A P value of less than 5% was considered statistically
`significant. SAS (version 9.1, Cary, NC) was used for
`statistical analyses.
`
`Results
`
`Aim 1. There were 54 compounds in the 10 mg/day
`or less group, 83 in the 11-mg to 49-mg/day group, and
`93 in the 50 mg/day or greater group (Table 2). In 2005,
`the total number of prescriptions written ranged from
`1,258,000 to 34,230,000 for the 10 mg/day or less group,
`1,260,000 to 47,829,000 for the 11-mg to 49-mg/day
`group, and 1,286,000 to 101,639,000 for the 50 mg/day
`or greater group. There was no statistically significant dif-
`ference in the median number of prescriptions written in
`2005 among these three groups (P ⫽ 0.37; Table 3).
`There was a statistically significant relationship be-
`tween recommended daily dose and reports of liver fail-
`
`ure, liver transplantation, or liver-related death (Tables 3
`and 4). Seventeen percent of compounds belonging to the
`10 mg/day or less group had been reported to cause liver
`failure, in comparison with 12% in the 11-mg to 49-mg/
`day group and 32% in the 50 mg/day or greater group
`(P ⫽ 0.009). No compounds belonging to the 10 mg/day
`or less group caused liver transplantation, in comparison
`with 2% in the 11-mg to 49-mg/day group and 14% in
`the 50 mg/day or greater group (P ⬍ 0.001). Eleven per-
`cent of compounds belonging to the 10 mg/day or less
`group and the 11-mg to 49-mg/day group were reported
`to have caused DILI-related deaths, in comparison with
`28% of compounds belonging to the 50 mg/day or greater
`group (P ⫽ 0.007). There was no statistically significant
`
`Table 4. Relationship Between Daily Dose and Different
`Hepatic Events: Results from the Logistic Regression
`Analysis
`
`Outcome and Covariate
`
`Odds
`Ratio
`
`95% Confidence
`Interval
`
`P-Value
`
`ALT ⬎ 3 ⫻ ULN
`Compound
`ⱕ 10 mg
`11–490 mg
`ⱖ50 mg
`Jaundice
`Compound
`ⱕ10 mg
`11–49 mg
`ⱖ50 mg
`Liver failure
`Compound
`ⱕ10 mg
`11–49 mg
`ⱖ50 mg
`Death
`Compound
`ⱕ10 mg
`11–49 mg
`ⱖ50 mg
`Transplant
`Compound
`⬍50 mg
`ⱖ 50 mg
`
`1.00
`1.59
`1.99
`
`1.00
`1.32
`1.65
`
`1.00
`0.69
`2.38
`
`1.00
`0.97
`3.10
`
`1.00
`10.00
`
`0.68–3.68
`0.88–4.50
`
`0.65–2.70
`0.82–3.31
`
`0.26–1.81
`1.03–5.50
`
`0.33–2.91
`1.19–8.12
`
`0.28
`0.10
`
`0.45
`0.16
`
`0.446
`0.042
`
`0.961
`0.021
`
`2.18–45.8
`
`0.003
`
`Page 4 of 7
`
`

`
`HEPATOLOGY, Vol. 47, No. 6, 2008
`
`LAMMERT ET AL.
`
`2007
`
`Table 5. Types of Liver Injury and Outcome Stratified
`According to Daily Dose: The Swedish Hepatic ADR Data
`(Total Eligible Cases ⴝ 598)
`<10 mg/day 11–49 mg/day >50 mg/day
`
`Number of DILI cases
`Pattern of injury
`Hepatocellular
`Cholestatic
`Mixed
`Outcome
`Death/liver transplantation*
`Survived
`Top 200 prescribed
`medicines in Sweden
`in 2005
`Proportion belonging to
`each dose group
`Median # of prescriptions
`
`53 (8.9%)
`
`85 (14.2%)
`
`460 (76.9%)
`
`34 (64.2%)
`13 (24.5%)
`6 (11.3%)
`
`43 (50.6%)
`22 (25.9%)
`20 (37.8%)
`
`231 (50.2%)
`124 (26.9%)
`104 (22.6%)
`
`1 (2%)
`52 (98%)
`
`8 (9.4%)
`77 (90.6%)
`
`61 (13.2%)*
`399 (86.8%)
`
`22.5%
`249,197
`
`27.5%
`360,149
`
`37.5%
`215,760
`
`*The proportion of patients who died/transplanted due to DILI was significantly
`higher in the ⱖ50 mg daily dose in comparison with the 11– 49 mg/day and the
`ⱕ10 mg/day groups (13.2% versus 9.4% versus 2%. P ⫽ 0.03).
`
`association between daily recommended dose of oral pre-
`scription medications and reports of ALT more than 3⫻
`the upper limit of normal or jaundice (Tables 3 and 4).
`The logistic regression analyses showed that a signifi-
`cantly higher proportion of medications belonging to the
`50 mg/day or greater group had liver failure (odds ratio,
`2.38; 95% confidence interval, 1.03-5.50), liver trans-
`plantation (odds ratio, 10.00; 95% confidence interval,
`2.18-45.81), or liver-related death (odds ratio, 3.10; 95%
`confidence interval, 1.19-8.12), whereas medications be-
`longing to the 10 mg/day or less and 11-mg to 49-mg/day
`groups had no differences (Table 4).
`Aim 2. After applying exclusion criteria to Swedish
`DILI death/transplant and jaundice cases, a total of 598
`cases were eligible for further analyses (58% females, me-
`dian age of 59 years (interquartile range, 42-74); 51% had
`hepatocellular type and 49% had cholestatic/mixed type
`of liver injury. Seventy-seven percent of Swedish DILI
`cases belonged to the 50 mg/day or greater group, whereas
`
`only 9% belonged to the 10 mg/day or less group, and
`14% belonged to the 11-mg to 49-mg/day group (Table
`5). The pattern of liver injury and patient outcomes in
`different dose categories are shown in Table 5. Only one
`patient treated with 10 mg/day or less died, and only very
`few other patients with a lower daily dose than 50 mg/day
`either died or underwent liver transplantation (Table 5).
`A statistically significant relationship was noted between
`daily dose and poor outcome (death or liver transplanta-
`tion) of Swedish DILI cases (13.2%, 9.4%, and 2% in
`ⱖ50, 11-49, and ⱕ10 mg/day groups, respectively; P ⫽
`0.03). Selected details of patients belonging to the 10
`mg/day or less group and the 11-mg to 49-mg/day group
`who had poor outcome after DILI event are shown in
`Table 6. As a control measure, we assessed the proportion
`of prescription medications and their prescription volume
`in Sweden that belong to each of these dosage groups.
`After excluding nonoral formulations from 200 most pre-
`scribed medicines in Sweden in 2005, 37.5% belonged to
`the 50 mg/day or greater group, 27.5% belonged to the
`11-mg to 49-mg/day group, and 22.5% belonged to the
`10 mg/day or less group. The median number of prescrip-
`tions written in 2005 in Sweden were 249,197 (range,
`101,094-1,847,843) for the 10 mg/day or less group,
`360,149 (range, 99,986-2,647,547) for the 11-mg to 49-
`mg/day group, and 215,760 (range, 104,073-3,601,864)
`for the 50 mg/day or greater group.
`Of 137 non-APAP DILI cases that required liver trans-
`plantation in the United States between 1990 and 2002,
`after excluding cases caused by inhalation agents (n ⫽ 4),
`intravenous agents (n ⫽ 3), herbal agents (n ⫽ 7), aman-
`ita mushrooms (n ⫽ 9), and combination of agents (n ⫽
`3), 111 cases were further analyzed. Of these 111 cases,
`two cases were caused by compounds belonging to the 10
`mg/day or less group, eight belonged to the 11-mg to
`49-mg/day group, and 101 cases were reportedly caused
`by compounds with a daily recommended dose of 50 mg
`or greater (Table 7).
`
`Table 6. Selected Details of Patients with Poor Outcome DILI (Death or Transplantation) Caused by Compounds Given at
`<50 mg Daily Dose: The Swedish Hepatic ADR Dataset
`Daily Dose
`Duration of Exposure
`(mg/day)
`(days)
`
`Type
`
`Outcome
`
`Sex/Age
`(yrs)
`
`Medication
`
`Male/79
`Male/64
`Female/73
`Male/63
`Male/64
`Female/74
`Male/78
`Female/55
`Female/73
`
`Donepezil
`Enalapril
`Omeprazole
`Simvastatin
`Rofecoxib
`Enalapril
`Simvastatin
`Hydralazine
`Dikumarol
`
`5
`10
`40
`20
`25
`30
`20
`25
`40
`
`HC, hepatocellular; CS, cholestatic; LT, liver transplantation.
`
`501
`60
`300
`90
`23
`60
`90
`180
`120
`
`HC
`Mixed
`HC
`HC
`HC
`HC
`HC
`HC
`CS
`
`Death
`LT
`Death
`LT
`LT
`Death
`Death
`Death
`Death
`
`Page 5 of 7
`
`

`
`2008
`
`LAMMERT ET AL.
`
`HEPATOLOGY, June 2008
`
`Table 7. DILI Requiring Liver Transplantation in the United
`States From 1990 to 2002 According to the UNOS Database
`Dosage Groups <10 mg/day
`>50 mg/day
`
`11–49 mg/day
`
`Cerivastatin (2)
`
`Individual agents
`(number of
`cases)
`
`Fialuridine (3)
`Lisinopril (1)
`Simvastatin (1)
`Pemoline (1)
`Zafirkulast (1)
`Paroxctine (1)
`
`Total number
`
`2
`
`8
`
`Isoniazid (24)
`Propylthiouracil (13)
`Phenytoin (10)
`Valproate (10)
`Nitrofurantoin (7)
`Ketoconazole (6)
`Disulfiram (6)
`Troglitazone (4)
`Sulfasalazine (3)
`Methyldopa (3)
`Nefazadone (2)
`Labetalol (2)
`Amoxicillin/Clavulan (1)
`Bromfenac (1)
`Ibuprofen (1)
`Hydrocodone (1)
`6-Mercaptopurine
`Itraconazole (1)
`Carbamazepine (1)
`Trimethoprim/Sulfametho
`Buproprion (1)
`Iron (1)
`Naproxen (1)
`101
`
`NOTE. Excluded are inhalation agents (4), intravenous agents (3), herbal agents
`(7), Amanita mushrooms (9), and combination of agents (3).
`
`Discussion
`Although idiosyncratic DILI is traditionally thought to
`be not dose-related, some experts have noted that most
`medications that have either been withdrawn or received
`black box warning because of hepatotoxicity were pre-
`scribed at daily doses greater than 50 mg (Table 1).4 This
`observation in conjunction with our own anecdotal expe-
`rience prompted us to search for any epidemiological sig-
`nals supporting such a relationship in the existing
`literature. Our study consisting of different data sets in-
`deed supports a relationship between the daily dose of an
`oral medication and its propensity to cause serious hepa-
`totoxicity.
`Using two comprehensive pharmacy databases, we ex-
`amined the relationship between recommended daily
`doses of 230 oral medications commonly prescribed in
`the United States and reports of selected hepatic adverse
`events. A significantly greater proportion of oral medica-
`tions belonging to the 50 mg/day or greater group were
`reported to cause liver failure and liver failure leading to
`death or liver transplantation than medications belonging
`to other two groups. There was a trend in the relationship
`between daily dose and reports of ALT greater than 3⫻
`ULN and jaundice, but they did not reach statistical sig-
`nificance. Because we had difficulty in distinguishing cho-
`lestatic and hepatocellular jaundice from the reports
`
`contained within the DRUGDEX, we included both cho-
`lestatic and hepatocellular cases in our jaundice category.
`This may explain in part why we failed to observe a sta-
`tistically significant relationship between daily dose and
`reports of jaundice in the US prescription medication
`data set. The results from the Swedish ADR data set are
`noteworthy in that 77% of all serious DILI cases belonged
`to the 50 mg/day or greater group. Furthermore, DILI
`events belonging to the 50 mg/day or greater group were
`more likely to lead to death or liver transplantation when
`compared with the other two groups combined. Further-
`more, US liver transplantation data also revealed that
`there is significant enrichment of DILI cases requiring
`liver transplantation in the 50 mg/day or greater group.
`It has been hypothesized that idiosyncratic DILI could
`either be attributable to hypersensitivity or to metabolic
`idiosyncracy.19 Our epidemiological study is not able to
`address whether the dose of a compound is more relevant
`for one particular mechanism of idiosyncratic DILI; how-
`ever, intuitively one may suggest that daily dose may be
`more relevant for metabolic idiosyncrasy rather than hep-
`atotoxicity caused by hypersensitivity. The categories of
`compounds known to cause idiosyncratic DILI at a
`higher frequency (for example, antibacterials, nonsteroi-
`dal anti-inflammatory drugs) were overrepresented in the
`50 mg/day or greater group. However, it is not known
`whether these categories of compounds are more hepato-
`toxic because their daily dose was often 50 mg or greater
`or whether the noted association between daily dose and
`DILI is driven by overpopulation of these categories in the
`50 mg/day or greater group. If confirmed by other studies,
`the noted association between daily dose and idiosyn-
`cratic DILI would support a reactive metabolite hypoth-
`esis for the pathogenesis of idiosyncratic DILI.
`Some aspects of our study deserve further discussion.
`First, this is a retrospective analysis of existing literature
`and thus its findings should be viewed as epidemiological
`signals rather than factual observations. However, ques-
`tions of this nature cannot easily be addressed by prospec-
`tive randomized studies because of
`the very rare
`occurrence of clinically significant hepatotoxicity. Sec-
`ond, because our study dealt exclusively with oral medi-
`cations, it is not possible to extrapolate our observations
`to parenteral, topical, or inhalation formulations. Finally,
`although 50 mg/day or greater appears to be the threshold
`daily dose beyond which the risk of DILI may be signifi-
`cantly higher compared with lower doses, it is not an
`absolute threshold. In other words, although serious DILI
`is rarely caused by compounds belonging to the 10 mg/
`day or less group, it is not that rare to exclude DILI as a
`possibility when an individual consuming a medication with
`a daily dose of 10 mg/day or less develops acute liver injury.
`
`Page 6 of 7
`
`

`
`HEPATOLOGY, Vol. 47, No. 6, 2008
`
`LAMMERT ET AL.
`
`2009
`
`We believe that our observations are worthy of further
`investigation. Proprietary data sets possessed by the pharma-
`ceutical companies, the Adverse Event Reporting System da-
`tabase, and prospective studies such as that conducted by the
`Drug Induced Liver Injury Network (DILIN) may provide
`additional opportunities to further explore this relationship.
`If these results are supported by other investigations, these
`observations are of importance in drug development to avoid
`problems with DILI in the future.
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