PREVENTABLE DRUG HARMS IN HEPATOBILIARY SYSTEM, A PROSPECTIVE OBSERVATIONAL STUDY IN OPD & IPD PATIENTS OF MEDICINE DEPARTMENT FROM CIVIL & PRIVATE HOSPITAL, NASIK

Desle RS, Khairnar A*

University Department of Health Sciences, Maharashtra University of Health Sciences, Nasik

Abstract

Hepatotoxicity is a potential adverse effect for commonly prescribed drugs & Liver is the main organ for metabolism of drugs therefore it is susceptible to high degree of toxicity. This study was done to study the frequency of drug induced liver injury and to find the common drugs causing hepatotoxicity. The study was conducted at Medicine Department from Civil & Private Hospital Nasik. This study was based on case series analysis. All patients with abnormal liver function reports were included in study. As it was a long term study therefore not possible to recruit all drug induced liver injury patients in shorter time period. Our total sample size is 180 out of which 70 (38.88%) patients were recruited within given time line. Out of total 70 Patients 46 were male (65.71%) & 24 were female (34.29%). The mean age of the patients with drug induced liver injury was 40.44 years Non steroidal anti-inflammatory drugs were commonly encountered drugs (24.29%) causing hepatotoxicity followed by antibiotics (20%). Other drugs included antitubercular drugs (11.43%), antimalarial drugs (10%), highly active anti-retroviral therapy drugs (5.71%), immunosuppressant’s (5.71%). In Most of the cases reported adverse drug reaction were probably preventable 43(61.42%) where as defiantly preventable were 8(11.42%) and remaining were not preventable 19(27.14%). Non steroidal anti-inflammatory drugs were most common hepatotoxic drugs.

Keywords: Drug induced liver injury, Hepatotoxicity, Non-steroidal anti inflammatory drugs, Antitubercular drugs, Highly active anti-retroviral therapy.

*Corresponding author:Khairnar AUniversity Department of Interpathy Research and Technology Maharashtra University of Health Science, Nasik, MaharashtraEmail: avinashkhairnar@gmail.com

Introduction:

An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dose1. In the United States, more than 100,000 deaths are attributed annually to serious adverse drug reactions2. 3 to 6 percent of all hospital admissions are because of adverse drug reactions, and 6 to 15 percent of hospitalized patients (2.2 million persons in the United States in 1994) experience a serious adverse drug reaction3, 4.

DILI can be defined as a liver injury induced by a drug or herbal medicines leading to liver test abnormalities or liver dysfunction with reasonable exclusion of other competing etiologies. Drug-induced liver injury (DILI) is a common liver disease which generally occurs between 5 and 90 days after drug ingestion5. Most cases of DILI are due to idiosyncratic or unexpected reactions. In contrast to paracetamol induced hepatotoxicity, which occurs with dose-dependent overdose of the drug, idiosyncratic drug reactions have been traditionally considered dose independent. Drug-induced liver injury (DILI) caused by idiosyncratic drug reactions is in most cases detected in a patient with mild to moderate elevations of liver tests, but can in rare cases lead to fatal hepatic necrosis6, 7.

Studies before the release of a drug are usually underpowered to detect rare side effects such as DILI and the information on these is usually obtained in the post marketing phase8. The real incidence of DILI remains unknown because of the difficulty in establishing diagnosis and the low reporting frequency to the Pharmacovigilance authorities. Only one prospective population based study has been undertaken in France till now to know the incidence of DILI which revealed incidence of 13.9 per 100000 inhabitants, result of this study was considered as gold standard for DILI9. From UK & Sweden also some prospective studies comes which shows incidence rate of 2-3 cases per 100000 inhabitants per year which is negligible10. Acute hepatic injury resulting from drugs has been reported to occurs in 2-10% of patient hospitalize for jaundice11.

Adverse drug reactions are an important cause of liver injury that may require discontinuation of the medicines, hospitalization, or even liver transplantation12. Drug-induced hepatotoxicity is the most frequent cause of acute liver failure, because the liver is responsible for concentrating and metabolizing a majority of medications, it is a prime target for medication-induced damage13.

The aims of the present study were to find out the frequency of DILI and to find the common drugs causing hepatotoxicity. Depending on the duration of injury and the histological location of damage, drug-induced liver injury (DILI) is categorized as acute or chronic, and either as hepatitis, Cholestatic, or a mixed pattern of injury. A broad range of different pharmacological agents can induce liver damage, including anticancer drugs, antibiotics, antituberculosis agents, antiretrovirals, and cardiac medications. In addition, a traditional medical therapies and herbal remedies may also be hepatotoxic.

Materials and Methods:

Study was conducted in compliance with the protocol, ICH GCP, ICMR, Schedule ‘Y’ guidelines and Indian regulatory requirements. This study was carried out in civil hospital and Private hospital, Nasik. Approval from Independent Ethics Committee was taken prior to initiation of the study. It was the prospective observational study based on case series analysis.

Signed dated written informed consent was taken from all subjects after providing them with patient information sheet and informed consent form before screening. Total sample size was 180 but within given time period it is not possible to complete the study, so 70 patients were recruited in study. All 70 patients had abnormal liver function test among these 46 were males & 24 were females. Total 70 subjects and their prescriptions in which 50 subjects was from medicine department of Civil hospital, Nasik and 20 was from private hospital, Nasik, all patients of abnormal liver function test was included in study. Screening of subjects was done according to inclusion and exclusion criteria with help of screening form and subjects were enrolled in study.

To identify DILI liver function test reports was screened having total bilirubin more than 1mg/dl or PT-INR more than 1.5 were included in study. DILI is categorized either as hepatitis, Cholestatic, or a mixed pattern of injury; also injuries are classified as mild, moderate and severe as per severity criteria. For the causality assessment WHO scale was used. Patients were analyzed for age, gender, history of drug intake. All the data were recorded on Case Record Form which is specially design for the study. Data analyzed using descriptive statistics.

RESULT:

It was the Prospective observational study carried out in civil hospital and Private hospital, at Nasik. Informed consent document was obtained from all patients enrolled in study. Over a period of 2 months total 70 patients are suspected for drug induced liver injury. In which 50(71.42%) patients were from civil hospital & 20(28.57%) patients from Private hospital. All 70 patients had abnormal liver function test, among these 46(65%) were males & 24(35%) were females. [fig. 1]

The mean age of all the patients was 40.44 + 4.24 years. Mean age for male was 39.63 + 4.24 and for female was 42 + 19.09 years (range from 18- 60 years). Drug induced liver injury was more common in males. [fig. 2] In this study we have found mainly three types of patterns of liver injury Hepatic, Cholestatic and Mixed. First one was Hepatic injury which accounts for 32 (45.7%) cases second one was Cholestatic injury which accounts for 6 (8.6%) cases and last one was mixed type of injury which accounts for 32 (45.7%) cases of DILI. In our study mixed and hepatic type of injuries are found equally while Cholestatic type was found in very few cases. [fig. 3]

In our study we found that following some drugs were commonly prescribed, which was responsible for causing drug induced liver injury. NSAIDS were 25% causing hepatotoxicity which includes drugs like Nimesulide, Diclofenac, Ibuprofen & Naproxen. After that Antibiotics were 20% causes DILI including Amoxicillin- clavulanic acid, Azithromycin, Ciprofloxacin, Erythromycin. Then Antitubercular drugs were 11% responsible for hepatotoxicity. Antimalarial drugs contribute 11% in DILI includes Falcigo & Artither. HAART & Immunosuppressant’s were 6% (each) responsible for hepatotoxicity includes drugs like-zidovudine, Abacavir, Nevirapine & Methotrexate. Another group of drugs which is 5% (each) responsible for DILI is Antifungal includes fluconazole & ketocanazole, Lipid lowering agents includes Atorvastatin & Antihypertensive includes Captopril. Antileprosy drugs were 3% responsible including Dapson. Some other drugs like anticonvulsant (valproic acid) anticoagulants (Heparin) antacids (Ranitidine) antidepressants (Olimet/zapiz) & Diuretics (Dytor) were 1% (each) responsible for hepatotoxicity. [fig. 4]

NSAIDS were 25% causing hepatotoxicity where Nimesulide was found responsible in total 8(11.42%) cases, Diclofenac was present in 6(8.57%) cases, Ibuprofen was present in 2(2.85%) cases & Naproxen was present in 1(1.42%) case. After that Antibiotic were 20% causes DILI, where Amoxicillin-clavulanic acid was present in 6(8.57%) cases, Ciprofloxacin was present in 4(5.71%) cases, Azithromycin was present in 2(2.857142857%) cases, Erythromycin was present in 1 (1.42%) case, and cefixime was present in 1 (1.42%) case. Then Antitubercular drugs were 11% responsible for hepatotoxicity. Antimalarial drugs were responsible in 11% case in DILI where Falcigo was present in 6(8.57%) cases, and Artither was present in 1 (1.42%) case. HAART drugs were responsible for hepatotoxicity in 4(5.71%) cases because of its combination preparation it was very difficult to assess individual drug. Immunosuppressants were also responsible for 4(5.71%) cases for causing hepatotoxicity includes drugs like- Methotrexate and Azathioprine. Methotrexate was accounts for 2(2.857142857%) cases, and Azathioprine was accounts for 2(2.857142857%) cases. Antifungal were 5% responsible for DILI where fluconazole was present in 2(2.857142857%) cases, & ketocanazole was present in 1 (1.42%) case. Lipid lowering agents were 5% responsible for DILI includes Atorvastatin & Antihypertensive were also 5% responsible for DILI includes Captopril. Antileprosy drugs were

3% responsible for DILI including Dapson. Other drugs like anticonvulsant (valproic acid) anticoagulants (Heparin) antacids (Ranitidine) antidepressants (Olimet/zapiz) & Diuretics (Dytor) were 1% each responsible for hepatotoxicity. [Table-1]

In total 70 cases we found 164 ADRs, from which in 39.03% ADRs serum bilirubin was elevated and the mean serum bilirubin was 3.19±1.95 mg/dl. In 20.73% SGPT/SGOT (AST/ALT) level were elevated and mean SGPT was 172±195 IU, and mean SGOT was 139.418± 178.809. In 22.56% hemoglobin level was decreased, mean of Hb was 8.85± 2.33 while in 7.31% each PT/INR & Platelets level was disturbed respectively. Only in 3.04% ADRs Total Leukocyte Count (TLC) was disturbed. [Table-2]

In over all study according to severity criteria we found mild, moderate and severe type of cases. In this study out of total 70 cases 49(70%) cases was mild type, in 18(25.7%) cases severity was moderate but 3(4.3%) cases was severe. In majority of the cases severity was mild, where as some of them were moderate very few severe cases was also found. [Table-3]

We use WHO causality assessment scale for the causality analysis. By using scale we found 36% cases were possible ADRs where as 33% cases cause was unlikely. In 20% case was probable ADRs and 6% cases were unclassified where as remaining 5% cases were unclassifiable. [fig. 5]

Preventability of ADRs was studied using modified Shumock and Thornton criteria. We found three types, defiantly preventable, probably preventable and not preventable. In Most of the cases reported ADRs were probably preventable 43(61.42%) where as defiantly preventable were 8(11.42%) and remaining ADRs were not preventable 19(27.14%). [fig. 6]

DISCUSSION:

This was the Prospective observational study conducted at civil and private hospitals of Nasik. The occurrence of 70 cases of drug induced hepatotoxicity within 2 months short period is accentuate the seriousness of problem. A specific drug may cause liver damage by many reasons. First, there are some drugs that are intrinsically toxic to the liver. These drugs can cause liver injury when the drug is taken in a dosage that exceeds the recommended dosage. This form of drug hepatotoxicity is known as “dose-dependent.” Second, there are some drugs that can trigger an idiosyncratic reaction (an abnormal, unexpected hypersensitivity), to a normal dose of the drug similar to an allergic reaction, even though a normal dose may be taken. Finally, a person’s susceptibility to a potentially hepatotoxic drug is enhanced by many factors. Some of these factors are within the person’s control, such as cigarette smoking and excessive alcohol intake. But other factors cannot be altered. These include advancing age and being of the female gender.

We found DILI as well as abnormal LFTs was more common in males than female, which was in accordance with the study conducted by Sgro et al. in France13. The expression of male predominance might be because of more male patients than female in our study. There are various studies which contradict our findings. The mean age for all patients with abnormal LFTs & DILI was 40.44 + 4.24 years. This might be because of advancing age, there is decrease clearance, decrease hepatic blood flow and low hepatic volume all these leads to increase risk of hepatic injury14.

The liver considered as the most important organ in drug toxicity for two reasons: on one hand it is functionally interposed between the site of absorption and the systemic circulation and is a major site of metabolism and elimination of foreign substances; but on the other hand these features also render it a preferred target for drug toxicity. Drug-induced liver injury therefore poses a major clinical problem. DILI is commonly classified into intrinsic vs. idiosyncratic hepatotoxicity; intrinsic hepatotoxicity is regarded as dose dependent and predictable, whereas idiosyncratic hepatotoxicity occurs without obvious dose-dependency and in an unpredictable fashion. DILI is divided into three types: hepatocellular, Cholestatic, and mixed according to the Councils for International Organizations of Medical Sciences (CIOMS).

In this study we have found mainly three types of patterns of liver injury where first one is Hepatic injury which accounts for 45.7% second one is Cholestatic injury which accounts for 8.6% and last one is mixed type of injury which accounts for 45.7% of DILI. Liver injury is likely to be more severe in hepatocellular type than in Cholestatic & mixed type and patients with elevated bilirubin levels in hepatocellular liver injury indicating serious liver injury with fatalities.

In this study we discussed about drugs suspected of being responsible for cases of DILI. Although drugs with a well-documented capacity to cause DILI can lead to a different expression in different patients, most hepatotoxic drugs have ‘signature’ toxicity. A hepatitic pattern is typically observed in patients with isoniazid, disulfiram and Diclofenac-associated hepatotoxicity, whereas Cholestatic injury is seen most often with amoxicillin ⁄ clavulanic acid and macrolide antibiotics2. In our study drugs like AKT, Amoxicillin, ciprofloxacin, Diclofenac were causing hepatic injuries where as HAART, Fluconazole, Azathioprine were responsible for Cholestatic type of injuries in our population.

A study by Chalasani et al. in USA shows drugs like Antibiotic’s, CNS agents, Herbs, Analgesics & Antihypertensive were responsible for DILI15. Our study shows that following some drugs are commonly prescribed, which was found responsible for causing drug induced liver injury. NSAIDS was 25% causing hepatotoxicity which includes drugs like Nimesulide, Diclofenac, Ibuprofen & Naproxen. After that Antibiotic was 20% causes DILI including Amoxicillin - clavulanic acid, Azithromycin, Ciprofloxacin, Erythromycin. Then Antitubercular drugs were 11% responsible for hepatotoxicity. Antimalarial drugs contribute 11% in DILI includes Falcigo & Artither. HAART & Immunosuppressant’s was 6% (each) responsible for hepatotoxicity includes drugs like-zidovudine, Abacavir, Nevirapine & Methotrexate. Another group of drugs which was 5% (each) responsible for DILI was Antifungal includes fluconazole & ketocanazole, Lipid lowering agents includes Atorvastatin & Antihypertensive includes Captopril. Antileprosy drugs are 3% responsible including Dapson. Some other drugs like anticonvulsant (valproic acid) anticoagulants (Heparin) antacids (Ranitidine) antidepressants (Olimet/zapiz) & Diuretics (Dytor) was 1% (each) responsible for hepatotoxicity. In a study conducted by De velle shows Antibiotic, Diclofenac, HIV drugs, Azathioprine, Atorvastatin were responsible for DILI cases1. Our study result was also in concordance with this study.

In our study we found that AKT drugs were one of the common causes for DILI. Because of its combination preparation it was difficult to identify individual drug responsible for DILI. This is in accordance with the study conducted by Kshirsagar et al. where they found antitubercular drugs as the common cause for drug induced hepatotoxicity7. These findings might be because of high incidence of tuberculosis in India, especially rural population. This could be because of low socioeconomic condition and unhygienic environment.

In overall study we found total 164 ADRs from the 70 cases. In most of the cases abnormal LFTs was found whereas in some cases elevated serum bilirubin level and PT/INR was present. Apart from this some concomitant ADRs like decrease Hb level & abnormal haematocrit values were also present in our study. DILI is underreported and neglected in rural areas and it is an important cause of acute liver failure in adults. In our study we classify severity in three types, Where 70% cases were mild, 25.7% cases were moderate and only 4.3% cases were the severe.

We have used WHO causality assessment scale for the causality analysis. The WHO-UMC system has been developed in consultation with the National Centers participating in the Programme for International Drug Monitoring and is meant as a practical tool for the assessment of case reports by using scale we found 20% case was probable ADRs, where as 36% cases was possible ADRs. In 33% cases cause was unlikely and 6% cases was unclassified where as remaining 5% cases was unclassifiable.

Preventability of ADRs was studied using modified Shumock and Thornton criteria. Most of the cases reported ADRs were probably preventable i.e. 61.42% where as definitely preventable were 11.42% and in remaining cases ADRs were not preventable.

Behind conducting this study our objective was to identify preventable ADRs and improve public health and safety in relation to use of medicine, but our study was conducted for short period of time and including few patients. For the better understanding of preventable drug harms similar studies are needed which covering more patients for longer period of time.

Conclusion:Hepatotoxicity is the one of the largest problem in community now a day. In many diseases liver is the target organ which is very important for survival. By medication Doctor helps liver to recover faster, but in case prescribed drugs causing harm to liver the chances of recovery become very few. So before prescribing any drug physician have to check all the effects of drug on human body. After this study we can say there are many commonly prescribed drugs which can easily cause harm to liver. In this series NSAIDS, some Antibiotics & Antitubercular drugs are the first rank drugs.

Acknowledgements:We are immensely thankful to our esteemed guide Dr. Avinash Khairnar, Asst. Professor University Department of Interpathy Research & Technology MUHS, Nashik for his constructive criticism, perpetual encouragement, timely advice and meticulous attention were the real driving forces as well as his keen interest in our project encouraged us a lot. We are very grateful to staff of civil hospital, Nasik for their cooperation in collecting data of the patients.

REFERENCES:

1) De Valle MB, Klinteberg VA, Alem N, Olsson R & Bjo¨ Rnsson E, Drug-induced liver injury in a Swedish University hospital out-patient hepatology clinic Aliment Pharmacol Ther, 2006, 24, 1187–1195

2) Larrey D. Epidemiology and individualsusceptibility to adverse drug reactionsaffecting the liver. Semin Liver Dis 2002; 22: 145–55.

3) Ditto AM. Drug allergy. In: Grammer LC, Greenberger PA, eds. Patterson's Allergic diseases. 6th ed. Philadelphia: Lippincott Williams & Wilkins 2002; 295.

4) Einarson TR. Drug‐related hospital admissions. Ann Pharmacother 1993; 27: 832‐40. Farrell GC Criteria of drug induced liver dis. London Church hill living stone 1994.

5) Kazuto Tajiri Yukihiro shimizu, Practical Guideline for Diagnosis & Early Management of Drug induced liver inj. 2008: 6774-85[Pubmed:19058303].

6) Bjornsson E, Olsson R. Outcome and prognostic markers in severe drug-induced liver disease. Hepatology 2005; 42:481–9.

7) Kshirsagar NA, Karande SC, Potkar CN. A prospective study of drug induced hepatotoxicity in large hospital. Indian J. Gastroenterol. 1992;1:13-5.

8) Lee WM. Assessing causality in drug-induced liver injury. J Hepatol 2000; 33: 1003–5.9) Ostapowicz G Fontana RJ Schiodtfv etc. Al Result of prospective study of acute liver

failure at 17 tertiary care centre in US Annual inter med 2002: 37:947-54[PubMed:12484709].

10) De Abajo FJ, Montero D, Madurga M, Rodriguez LAG. Acute and clinically relevant drug-induced liver injury: a population based case–control study. Br J Clin Pharmacol 2004; 58: 71–80.

11) Bjorneboe M, Iversen O, Olsen S. Infectivehepatitis and toxic jaundice in a municipal Hospital during a five year period: Incidence and prognosis. Acta Med Scand 1967; 182: 491–501.

12) Rolf Teschke, Alexander schwarzenboeck & Karei Heinz henermann, casuality assessment in hepatotoxicity by drug & Dietary Supplement, BJCP. 2008: 66:6 / 758-766.

13) Sgro C, Clinard F, Ouazir K, Chanay H, Allard C, Guilleminet C, Lenoir C, Lemoine A, Hillon P. Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology 2002; 36: 451-455.

14) Lewis JH. Drug induced liver disease. Med Clin North AM 2000;5:1275-311.15) Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, et al.

Causes, clinical features, and outcomes from a prospective study of drug induced liver injury in the United States. Gastroenterology 2008; 135:1924-1934.

66%

34%

PREVALANCE OF DILI

MALEFEMALE

FIGURE NO.1: PREVALENCE OF DRUG INDUCED LIVER INJURY

FIGURE NO.2: AGE DISTRIBUTION OF STUDY POPULATION

6

46%

32

PATTERN OF DILI

CholestaticHepaticMixed

FIGURE NO.3: PATTERN OF DRUG INDUCED LIVER INJURY

NSAIDs

Antibiotics AKT

Antimalaria

l

HAART

Immuno Su

pressan

t

Antifungal

Antihypert

ensiv

e

Lipid lo

wering a

gent

Antilepro

sy

Antacid

Anticoag

ulant

Anticonvu

lsion

Antidepres

sant

Diuretics

0

2

4

6

8

10

12

14

16

18

DRUGS CAUSING DILI

Total

FIGURE NO.4: DRUGS CAUSING DRUG INDUCED LIVER INJURY

Serial No.

Drug Class Drug Name NO. of cases Percentage

1 NSAIDs Nimesulide 8 11.42857143Diclofenac 6 8.571428571Ibuprofen 2 2.857142857Naproxen 1 1.428571429

2 Antibiotic Amoxicillin 6 8.571428571Ciprofloxacin 4 5.714285714Azithromycin 2 2.857142857Erythromycin 1 1.428571429Cefixime 1 1.428571429

3 AKT Combination 8 11.428571434 Antimalarial Falcigo 6 8.571428571

Artisunate 1 1.4285714295 HAART Combination 4 5.7142857146 Immunosuppressant Methotraxate 2 2.857142857

Azathioprin 2 2.8571428577 Antifungal Fluconazole 2 2.857142857

Ketoconazole 1 1.4285714298 Antihypertensive Captopril 3 4.2857142869 Lipid lowering agent Atorvastatin 3 4.28571428610 Antileprosy Dapson 2 2.85714285711 Antacid Ranitidine 1 1.42857142912 Anticoagulant Heparin 1 1.42857142913 Anticonvulsion Valproic Acid 1 1.42857142914 Antidepressant Alprazolam 1 1.42857142915 Diuretics Torsemide 1 1.428571429

TABLE 1: NO. OF CASES OBSERVED IN HOSPITAL

DRUG CLASS DRUGNo. of ADRs

LIVER ENZYME

PT/INR

S. BILI. Hb TLC Platelets

NSAIDs Nimesulide 19 6 0 8 5 0 0

Diclofenac 8 0 2 4 2 0 0

Ibuprofen 4 0 0 2 2 0 0

Naproxen 2 0 0 1 1 0 0

ANTIBIOTIC Amoxy-Clav 16 5 0 6 3 0 2

Ciprofloxacin 9 3 0 4 2 0 0

Azithromycin 5 0 1 2 1 0 1

Erythromycin 1 0 0 1 0 0 0

Cefixime 3 1 0 1 1 0 0

AKT AKT 17 5 1 8 3 0 0

ANTIMALARIAL Falcigo 20 5 2 5 1 3 4

Artisunate 2 0 1 0 0 0 1

HAART HAART 9 1 0 4 3 0 1

IMMUNOSUPPRESANT Methotrexate 4 1 0 2 1 0 0

Azathioprine 5 1 0 2 2 0 0

ANTIFUNGAL Fluconazole 6 1 0 2 2 1 0

Ketocanazole 1 0 0 1 0 0 0

ANTIHYPERTENSIVE Captopril 7 0 1 3 2 1 0

LIPID LOWERING Atorvastatin 9 2 1 3 1 0 2

ANTILEPROSY Dapsone 4 0 0 2 2 0 0

ANTACID Ranitidine 3 1 0 1 1 0 0

ANTICOAGULANT Heparin 1 0 1 0 0 0 0

ANTICONVULSION Valproic Acid 3 1 0 1 1 0 0

ANTIDEPRESSANT Alprazolam 1 0 1 0 0 0 0

DIURETIC Torsemide 5 1 1 1 1 0 1

TOTAL 164 34 12 64 37 5 12

TABLE 2: NO. OF ADRS PER DRUG OBSERVED IN HEPATOBILIARY PATIENTS:

Intensity Frequency Percent Cumulative Percent

Mild 49 70.0 70.0

Moderate 18 25.7 95.7

Severe 3 4.3 100.0

Total 70 100.0

TABLE 3: SHOWING SEVERITY OF DRUG INDUCED LIVER INJURY

Possible Probable Unclassifiable Unclassified Unlikely0

5

10

15

20

25

30

25

14

3 4

24

CAUSALITY ASSESSMENT

Frequency

FIGURE NO 5: CAUSALITY ASSESSMENT USING WHO SCALE

Defiantly Preventable

Probably Preventable

Not Preventable

0 5 10 15 20 25 30 35 40 45 50

8

43

19

PREVENTABILITY OF ADRs

Number of cases

FIGURE NO 6: PREVENTABILITY OF ADRs