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Pattern of cutaneous adverse drug reactions at a tertiary care hospital in southern India

Adverse drug reaction (ADR) is defined as “an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product.” 1 ADRs are seen in increasing numbers in patients both hospitalized, and in those on outpatient care. 2-6 It is also well known that ADRs contribute significantly to hospital admissions. 7 ADRs as such is a cause of significant economic burden because it has been proven that hospitalization cost of patients who experience ADRs is comparatively more, than their counterparts who don’t. 8 It is also a significant burden economically to health care providers as well. 9,10 Many studies have shown that cutaneous drug reactions are one of the most frequently encountered ADRs during patient care. 11,12 Since there is an advent of newer drug molecules periodically and change in treatment protocols, it is prudent to evaluate the cutaneous ADRs (CADRs) continually. 13 Information obtained through such studies can give inputs on those ADRs that can be avoided with an increase in the quality of health care, apart from bringing down the costs involved in their management. 14


INTRODUCTION
Adverse drug reaction (ADR) is defined as "an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product." 1 ADRs are seen in increasing numbers in patients both hospitalized, and in those on outpatient care. [2][3][4][5][6] It is also well known that ADRs contribute significantly to hospital admissions. 7 ADRs as such is a cause of significant economic burden because it has been proven that hospitalization cost of patients who experience ADRs is comparatively more, than their counterparts who don't. 8 It is also a significant burden economically to health care providers as well. 9,10 Many studies have shown that cutaneous drug reactions are one of the most frequently encountered ADRs during patient care. 11,12 Since there is an advent of newer drug molecules periodically and change in treatment protocols, it is prudent to evaluate the cutaneous ADRs (CADRs) continually. 13 Information obtained through such studies can give inputs on those ADRs that can be avoided with an increase in the quality of health care, apart from bringing down the costs involved in their management. 14 The purpose of the current study is to elicit the pattern of CADRs, the drugs responsible and the age and gender based incidence of such reactions, in patients treated at a public tertiary care hospital in the southern part of India.

METHODS
A retrospective analysis of the CADRs retrieved from the Pharmacovigilance center database reported by active surveillance was carried out. The data pertains to the period from March 2013 to December 2015. The CADRs obtained so were confirmed by a team consisting of a senior dermatologist and pharmacologists.
The CADRs were grouped as certain, probable, possible, unlikely, unclassified, and unclassifiable based on the WHO causality assessment criteria. Only those CADRs classified as certain, probable and possible were included in this study. The pattern of CADRs and the drugs causing them, as well as the age and gender wise incidence of CADRs were analysed from the above mentioned data.
The data was entered in MS excel and analyzed using SPSS v20.0. The data was summarized using means and proportions.

RESULTS
During the above said period a total of 510 ADRs were reported, of which 388 (76.08%) were CADRs. Among these CADRs, only 293 (75.5%) were taken for analysis, as they satisfied the above mentioned WHO criteria ( Figure 1).  Among these 135 were seen in males, 151 were seen in females. They were grouped into paediatric (0-18), adult  and geriatric (60 and >) age groups. Most of the CADRs were reported in the adult age group (Table 1).
In the age and sex wise distribution of ADRs (Table 4), again it was found that urticaria/angioedema were the most common CADRs followed by generalised pruritis. The most common drugs to cause such reactions were again found to be antimicrobials.

DISCUSSION
CADRs are the most common ADRs when compared with the prevalence of other ADRs. 12 The cost involved in their management is significantly more for both the patients and health care providers.   Moreover they pose a significant threat to the health of the patients as CADRs may even be life threatening. A constant monitoring of CADRs is a must, since identification of potential ones and newer ones would pave way to prevent or avoid them.
As per the WHO causality criteria, most of the CADRs taken for analysis came under the probable causality, similar to the study done by Chatterjee et al. 6 As far as the age wise distribution, most of them were observed in the adult age group population. Similar results were seen in other studies. 4,13 This could be because of the fact that the health seeking behaviour of the adult age group is more when compared to their paediatric and geriatric counterparts.
In our study the females had a slightly higher incidence than the males with a ratio of 1:0.89, similar to the other studies conducted elsewhere. [15][16][17][18] Among the drugs causing the CADRs, the most common drug groups involved were antimicrobials. This is similar to many studies conducted elsewhere. 3,5,[18][19][20][21][22] The NSAIDs followed them as the next common drug groups to cause CADRs, similar to other studies. 12,18 Among the antimicrobials ciprofloxacin was the most common drug involved followed by cefotaxime. This again was similar to the study conducted by Vijeya kumar et al and similar results were obtained from the study by Qayoom et al, where quinolones were followed by cephalosporins as the most common antimicrobial groups involved. 18,19 This was in contrast to other studies where sulphonamides were the leading cause. 12,13 The difference in the pattern of antimicrobials between different studies could be due to the differences in the physician's preferences in using various antimicrobials and the varied disease prevalence from region to region. 4 In the present study, urticaria/angioedema was the most common CADR detected followed by generalised pruritis and fixed drug eruption. Similar results were obtained in one study, where urticaria was the leading CADR. 23 This is different from the other studies where maculopapular rash was the leading cause and fixed drug eruption in some. 4,5,13,18,22 The difference could be due to varied disease prevalence from place to place and the use of different kind of drugs for their appropriate management. In many of the studies describing CADRs, the most common CADRs were caused by antimicrobials. 3,5,13,18,19,22 The reason for this could be due to the fact that antimicrobials are the most commonly used drugs among other drugs since infectious diseases are one of the most common ailment which patients present with, and apart from that they are also frequently used prophylactically both before and after surgical procedures. In many studies quinolones were the most common antimicrobials involved. 18,19 The reason for this could be due to the fact that, quinolones being broad spectrum antimicrobials are the most frequently prescribed antimicrobials by clinicians.
Among the severe CADRs we had six cases of Stevens -Johnson syndrome, of which 4 cases were due to antiepileptics and 2 were due to antimicrobials. There were six cases of Erythema multiforme, all were caused by antimicrobials. This widely correlates with many studies where anticonvulsants and antimicrobials were the frequently involved drugs in causing such severe CADRs. 5,13,18 In the age wise distribution urticaria/angioedema was the most common CADRs in all the age groups, followed by generalised pruritis. The drugs most commonly involved in the most frequent CADRs in all the age groups were again found to be antimicrobials.
In the sex wise distribution the female sex had marginally more incidences of CADRs compared to males. In both the sexes the most common CADRs were urticaria/angioedema followed by generalised pruritis. In both the sexes, in all the frequent CADRs, the most common drug groups involved were again antimicrobials.

CONCLUSION
As CADRs are the most common ADRs among others, it is prudent to monitor them closely, as any change in pattern with older or newer agents can alert the health care personnel in instituting the appropriate prescription patterns, which can overall impact the quality of health care positively.