Indian Journal of Pharmacology Medknow Publications on behalf of Indian Pharmacological Society ISSN: 0253-7613 EISSN: 1998-3751 Vol. 36, Num. 5, 2004, pp. 292-295

Indian Journal of Pharmacology, Vol. 36, No. 5, October, 2004, pp. 292-295

Research Paper

Cutaneous adverse drug reactions in hospitalized patients in a tertiary care center

Noel MV, Sushma M, Guido S

Department of Pharmacology, St. John's Medical College, Bangalore - 560 034
Correspondence Address:Department of Pharmacology, St. John's Medical College, Bangalore - 560 034 noelonline@rediffmail.com

Code Number: ph04100

ABSTRACT

INTRODUCTION

MATERIAL AND METHODS

The study was prospective, done over a period of one year (October 1, 2002 to September 30, 2003) in the Dermatology Department of St. John′s Medical College Hospital, Bangalore. Institutional Ethical Review Board approval was obtained before starting the study. The data of in-patients of the Department of Dermatology who experienced ADRs and the in-patients transferred from other departments due to ADRs to the Dermatology Department were collected and analyzed on a daily basis by the principal investigator. The patients treated on an outpatient basis were excluded from the study. The diagnosis of the cutaneous ADR was done by a consultant dermatologist based on clinical and morphological grounds. ADR was defined as per the definition provided by WHO.[3] In every patient, the primary investigator collected a detailed history regarding drug intake, reaction time, previous allergic history, duration of reaction, type of cutaneous reaction, relevant investigations (blood culture and/ or serology to rule out infectious etiology), improvement after dechallenge, in a specially designed proforma. The criteria for the diagnosis of ADRs were as given below:

1. The time interval between the introduction of the drug and the onset of a reaction should be within a specific time described in the literature for each reaction (Maculopapular rash: <7 days, Urticaria: 7-21 days, SJS, TEN, Erythema multiforme: 1-3 weeks, Drug hypersensitivity syndrome: 2-6 weeks, Photodermatitis: up to 1 year, Exfoliative dermatitis: 1-6 weeks, Fixed drug eruption: 30 min-16 h). The reaction was not considered as drug-induced if the drug was administered after the onset of cutaneous reaction.
2. Improvement in the condition of the patient after dechallenge/ withdrawal of the suspected drug.
3. Drug rechallenge producing similar reaction again. This was not undertaken in any of our cases because of the possible associated risks.

Based on the WHO causality definitions,[3] ADRs were categorized as certain, probable, possible and unlikely. The definitions as provided by the WHO collaborating center are given below:

Certain: A clinical event, including laboratory test abnormality, occurring in a plausible time relationship to drug administration, and which cannot be explained by concurrent disease or other drugs or chemicals. The response to the withdrawal of the drug (dechallenge) should be clinically plausible. The event must be definitive pharmacologically or phenomenologically, using a satisfactory rechallenge procedure if necessary.

Probable/Likely: A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, unlikely to be attributed to the concurrent disease or other drugs or chemicals and which follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition.

Possible: A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, but which could also be explained by concurrent disease or other drugs or chemicals. Information on the drug withdrawal may be lacking or unclear.

Unlikely: A clinical event, including laboratory test abnormality, with a temporal relationship to drug administration which makes a causal relationship improbable, and in which other drugs, chemicals or underlying disease provide plausible explanations.

Only certain and probable cases were considered for analysis and the data was subjected to descriptive analysis.

RESULTS

A total of 557 patients (including those who were transferred from other departments) were admitted to the Department of Dermatology during the study period, of which 56 patients were diagnosed as cutaneous ADRs. Hence 8.25% of the hospitalized patients in the Department of Dermatology experienced cutaneous ADRs. According to the final causality assessment, one patient was classified under the category of certain, as rechallenge data was available (this patient was a case of Fixed drug eruption to metronidazole who was administered the drug for the second time unknowingly), 45 as probably associated as only dechallenge data was available and 10 as having possible association with the drug, as dechallenge data was not available. Therefore, only the certain and probable category of patients were considered for analysis which accounted for 46 patients. The male: female ratio was 1:1. The maximum number of reactions were seen in patients in the age group of 21-40 years.

Details of the clinical spectrum of cutaneous ADRs with the implicated drugs are presented in [Table - 1]. Maculopapular rash was the most common manifestation of cutaneous ADRs accounting for 35% of patients, followed by TEN in 20%, SJS in 15%, urticaria and erythema multiforme in 7% each, and drug hypersensitivity syndrome (DHS), photodermatitis, exfoliative dermatitis and fixed drug eruption (FDE) in 4% each. Antiepileptics, mainly phenytoin and carbamazepine were responsible for causing maximum number of maculopapular rash (56%), TEN (55%) and SJS (43%). Urticaria was caused mainly by paracetamol and exfoliative dermatitis by phenytoin. Phenytoin and paracetamol produced a wide spectrum of cutaneous ADRs (4 types each). As a group, antiepileptics were implicated in the majority of the patients (44%), followed by chemotherapeutic agents (32%) and NSAIDs (11%). Among antiepileptics phenytoin caused maximum number of ADRs (45%), followed by carbamazepine (30%). Among chemotherapeutic agents cotrimoxazole and dapsone were incriminated in many patients (21% each), followed by amoxicillin (14%). There was one death reported (2%) due to SJS induced by leflunomide.

Reaction time (RT) i.e. the time taken for the reaction to appear since the last exposure to the suspected drug was observed to be 2-7 days for maculopapular rash, 2-3 weeks for TEN, 1-3 weeks for SJS, 1-3 days for urticaria, 1-2 weeks for erythema multiforme, 1-4 weeks for DHS, 3-4 weeks for photodermatitis, 6 weeks for exfoliative dermatitis and 1 day for FDE.

DISCUSSION

Hutchison described causality assessment as a "method for eliciting a state of information about a particular drug-event connection as input and delivering as output a degree of belief about the truth of the proposition that the drug caused the event to occur".[2] There is no gold standard investigation for confirmation of a drug-induced reaction. Instead diagnosis and assessment of a drug cause involve analysis of a constellation of features such as timing of drug exposure and reaction time, course of reaction with drug withdrawal/ discontinuation, timing and nature of a recurrent eruption on rechallenge, a history of similar reaction to the suspected drug and previous reports of similar reactions to the same drug.[4] In this study, WHO causality definitions were used to categorize the ADRs into certain, probable, possible and unlikely categories as it is a very simple and widely accepted method to assess causality.

We found an equal incidence of ADRs in males and females, which is different from a study done in a North-Indian tertiary care center which reported male preponderance.[5] Among various age groups, the preponderance was in young adults, which is in keeping with other Indian studies.[5],[6] Cutaneous ADRs in other studies were observed in 2-3% of the hospitalized patients,[6] while in our study it was 8.25%. The RT observed for all the reactions in the present study was in accordance with previous reports, which further confirms the causality of the drug.[7]

A wide clinical spectrum of cutaneous ADRs was noticed in this study. Maculopapular rash (35%) was the commonest reaction encountered as cited in the literature.[5],[8] This was followed by TEN and SJS, which were found in 20% and 15% of the patients respectively. A high incidence of TEN and SJS has been reported from a North-Indian hospital,[9] while western studies[10],[11] have shown very low incidence as shown in [Table - 2].

Among the etiological drugs, antiepileptics, mainly phenytoin and carbamazepine were responsible for the majority (44%) of the ADRs. This was followed by chemotherapeutic agents (32%), mainly cotrimoxazole and amoxicillin. The next major group of drugs implicated was NSAIDs (11%), mainly paracetamol. Previous studies, in contrast, have shown antimicrobial agents to be the major causative agents.[5],[6],[8]

In this study, adverse cutaneous reactions to many newer molecules were detected, such as SJS to leflunomide, cefotaxime, and lamotrigine, and azithromycin-induced erythema multiforme, which have not been reported from India so far. The patient with leflunomide-induced SJS was on an irrational prescription and expired due to complications following SJS. Another interesting point brought out by this study was the association of the most commonly used drug, paracetamol, with various reactions like SJS, TEN, urticaria and fixed drug eruption. Glibenclamide, an antidiabetic drug induced erythema multiforme and photodermatitis as it is a sulfonamide derivative.[12] The incidence of dapsone syndrome was lower compared to a report from a South-Indian hospital.[13]

Dechallenge of the offending drug was done in all the cases immediately after identification of the ADR and the patients were treated appropriately. Severe cases were effectively managed and closely monitored till discharge.

In conclusion, the occurrence of cutaneous ADRs in the present study was similar in many ways to the other studies conducted in India. A wide clinical spectrum of cutaneous ADRs ranging from mild maculopapular rash to serious SJS and TEN was observed. The incidence of life-threatening cutaneous ADRs like SJS and TEN was found to be higher compared to studies published abroad. Antiepileptics were implicated in the majority of the cutaneous ADRs in hospitalized patients. Infrequently reported adverse reactions for newer drugs like leflunomide, cefotaxime and azithromycin were also detected in the present study.

REFERENCES

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