DOI: 10.7860/JCDR/2016/16430.

7047
Original Article

Antecedent Drug Exposure Aetiology and

Pharmacology Section

Management Protocols in Steven-Johnson

Syndrome and Toxic Epidermal Necrolysis,
A Hospital Based Prospective Study

Samina Farhat1, Muddasir Banday2, Iffat Hassan3

ABSTRACT Results: A total of 52 hospitalized cases of cutaneous adverse

Aim: The study sought to identify the magnitude and drug reactions were reported during the study period. We
characteristic of severe cutaneous adverse reactions (SCAR’s) identified a total of 15 cases (28%) of SCAR’s involving
like Steven–Johnson syndrome (SJS) and Toxic Epidermal 9(17%) of SJS and 6 (12%) of TEN. SJS was seen in 2(22%)
Necrolysis (TEN). males and 7(78%) females. TEN was seen in all females
(100%) and in no male. Drugs implicated in causing these life
Materials and Methods: A prospective study was conducted threatening reactions were identified as anticonvulsant agents
by the Department of Pharmacology in association with like carbamazepine (CBZ), phenytoin (PHT) and Lamotrigine
Department of Dermatology in SMHS hospital. The study was (LTG), oxicam NSAID, Sulfasalazine and levofloxacin. Despite
carried out from June 2013-June 2015 on hospitalized cases higher reported mortality rates in SJS and TEN all patients
of cutaneous adverse drug reaction reporting in hospital. The survived with 2 patients surviving TEN suffered from long term
SCAR’s were reported in a structured questionnaire based on opthalmological sequelae of the disease.
adverse drug reaction (ADR) reporting form provided by the Conclusion: Present study suggest that drug induced cutaneous
Central Drug Standard Control Organization (CDSCO) Ministry eruptions are common ranging from common nuisance rashes
of Health and Family welfare, Government of India. The SCAR’s to rare life threatening diseases like SJS and TEN, SJS/TEN
were analysed for their characteristics, causality, severity and typically occur 1-3 weeks after initiation of therapy. Aromatic
prognosis. Causality assessment was done by using a validated AED’s, LTG, oxicam NSAID’s, sulfasalazine and levofloxacin
ADR probability scale of Naranjo as well as WHO Uppsala have a tremendous potential to trigger SCARS’s. To ensure safe
Monitoring Center (WHO-UMC) system for standardized case use of pharmaceutical agents and better treatment outcomes
causality assessment. The management protocol were analysed post marketing voluntary reporting of severe rare and unusual
for their clinical outcome through a proper follow up period. reactions remains inevitable.

Keywords: Anticonvulsants, Oxicam NSAIDs, Severe cutaneous adverse reactions (SCAR’s)

Introduction Moreover, since the treatment protocols are not well established
Adverse drug reactions (ADRs) are the inevitable consequence of with clear- cut outcome the patients were therefore, followed up to
pharmacotherapy. Cutaneous manifestations are among the most recognize the outcome and asses the development of complication
frequent adverse reaction to drugs [1]. Several multicentric trails sequelae which could be delayed but debilitating.
have established that acute cutaneous reaction to drugs affected
3% of hospital inpatients. Reactions usually occur a few days to MATERIALs AND METHODS
4 weeks after initiation of therapy [2]. SJS and TEN are two rare The study was carried out by the Department of Pharmacology
acute life threatening SCAR’s characterized by mucocutaneous and Dermatology in SMHS, Government Medical College, Srinagar,
tenderness, erythema, and extensive exfoliation and detachment of India. A prospective study was conducted between June 2013-
epidermis. SJS is characterized by <10% of body surface area of June 2015 which included patients who were admitted to the
epidermal detachment, SJS-TEN overlap by 10-30% and TEN by hospital with a diagnosis of various patterns of cutaneous adverse
>30%. SJS and TEN have an annual incidence of 1.2-6 and 0.4-1.2 drug reaction (CADR’s). These also included SJS/TEN patients as
per million people’s respectively. Both effect women more frequently an important group because of their rarity of occurrence. The study
than men with a ratio of 1.5:1 and the incidence increases with received an approval from college ethical committee.
age [3-6]. The average mortality rate is 1-5% for SJS and 25-35% Data collection and drug enquiry: After obtaining informed
for TEN. Elderly, immunocomprised and those on radiotherapy are consent a structured questionnaire was used to interview the
at higher risk. Around 100 drugs have been identified as causal patients clinically diagnosed as SJS/TEN with a definite antecedent
agents of SJS/TEN [3,4,7-12]. Most frequently implicated drugs
drug history. The questionnaire included the contents based on
are sulphonamides, antibiotics, oxicam NSAID’s, quinolones, AED’s
suspected ADR reporting form provided by CDSCO, Ministry of
and allopurinol [13].
Health and Family Welfare, Government of India. It was used to
In view of the above facts a prospective study was undertaken with gather information on patients preceding hospitalization. The
an objective to estimate risk of SJS and TEN associated with use drug history included brand/generic name of drug, manufacturer,
of specific drugs in patients of North Indian ethnic background. batch no, expiry date, timing of use, dose, indications, plasma

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 Samina Farhat et al., Antecedent Drug Exposure and Management in SJS and TEN www.jcdr.net

concentration of drug if available for low therapeutic range drugs, lamotrigine use. All the hospitalized patients of SJS/TEN survived
previous exposure and previous ADR if any. For seriously ill patients following discharge from the hospital.
and children to be interviewed patient medical record and family Among patients of TEN, 2 patients continued to suffer from ocular
members provided the information. In addition clinical examination complications (like chronic inflammation, fibrosis entropion, trichiasis
and laboratory parameters were also recorded in questionnaire. and symblepheron) and persistent mucosal lesions. Another patient
Causality assessment was performed using a Naranjo scored of levofloxacin induced TEN was complicated with sepsis.
algorithm [14]. This method incorporates ten questions or criteria
SJS patients did not leave any sequelae following discharge from
related to the ADR. Every question is provided with a particular score
hospital. On the basis of Naranjo algorithm SJS patients were
based on the presence or absence of those criteria. These criteria
classified as: 2 as possible; 5 as probable; and 2 as definite and
are: (i) Previous reports; (ii) Event after drug was administered; (iii)
TEN patients were classified as 1 as possible 2 as probable and 3
Event abate on drug removal; (iv) Reaction appeared when the drug
as definite.
was administered; (v) Other non-drug causes for the adverse event;
(vi) Was a toxic serum concentration noted; (vii) Reaction more A detailed overview of the SJS/TEN patients in the form of age,
severe with increased dose or less severe with decreased dose; sex, drug therapy, and dose, indicator of use, onset of reaction,
(viii) Did the reaction appear when a placebo was given; (ix) Does concomitant drug therapy and cutaneous manifestations is shown
patient have a history of similar reaction with drug or drug class; (x) in [Table/Fig-2].
ADR confirmed objectively.
Based on the scoring the probability that the adverse event was
Discussion
The results in [Table/Fig-2] suggest that in a series of cases short
caused by the drug was classified as definite (score ≥9), probable
term use of AED’s act as a culprit in 56% of SJS/TEN patients
(5-8), possible (1-4) or doubtful (≤0).
followed by NSAID’s use. The study revealed a mean age of 37
Moreover, a highly dependable WHO-UMC system [15] for case years in SJS/TEN patients. Aromatic anticonvulsants, lamotrigine,
causality assessment has also been applied to reinforce the reliability NSAID’s, sulfasalazine and quinolones are among the high risk
of the study. The various causality categories based on assessment medications most frequently associated with SJS/TEN [5,11,18,19].
criteria are certain, probable/likely, possible, unlikely conditioned/ Lamotrigine a phenyltriazine is a new anticonvulsant and has shown
unclassified and unassessable/unclassifiable. The rationale for its efficacy for prophylaxis of depression in bipolar disorders.
combining two tools is to overcome limitations associated with Our study reveals 2 cases of SJS and 2 cases of TEN which are
individual methods. In our study all patients of SJS/TEN were associated with LTG use and reaction occurs within 3 weeks after
evaluated for severity and prognosis by using SCORTEN prognostic the initiation of therapy. This is in conformity with other studies where
scoring system [16,17] that has been developed to correlate mortality LTG has strong association with SJS/TEN. In two cases of our
with selected parameters [Table/Fig-1]. The management protocol study valproate is a concomitant drug with LTG. Its concomitant use
would involve prompt identification and withdrawal of culprit drug with LTG significantly increases the risk for development of adverse
(s) followed by vigorous supportive care. The drug therapy included cutaneous reaction. [20]. Valproate increases plasma levels of LTG
systemic steroids in form of i.v. Dexamethasone or Hydrocortisone by inhibiting its metabolism [21,22]. Moreover, there have been
on short-term basis. several case reports on the short term use of LTG in association of
SJS and TEN [23-28].
RESULTS Other drugs including aromatic AED’s show an onset of reaction
A total of 52 patients were identified as CADR’s of which 15 cases
within 1-2 months. The results are obviously showing predilection
(28%) were SCAR’s of these 9 (17%) cases were diagnosed as SJS
for female gender. Despite, no evidence based medicine standards
and 6 (12%) cases as TEN. SJS was seen in 2 (22%) males and 7
of acceptance; present study reveals that all the patients responded
(78%) females while as TEN was diagnosed in females only.
well to short-term administration of systemic corticosteroids without
The study revealed that these events were associated more any mortality. In patients, where AED therapy were offending agents
commonly with short term therapy with agents like lamotrigine, the drugs were withdrawn immediately as a measure for prevention
carbamazepine, valproic acid and phenytoin. The other drugs of drug reaction and were switched to Levetiracetam and Clobazam
associated were levofloxacin, oxicam NSAID’s and Ibuprofen. The to maintain seizure free remission.
study revealed that almost all cases of SJS/TEN develop within
Since the uncertainty persists regarding the well defined treatment
two months of use of aromatic anticonvulsant and within 3 week of
modalities of SJS/TEN other treatment protocols besides system
corticosteroids are high dose immunoglobulin’s (IVIG) [29-31],
Prognostic factors Points thalidomide [32], cyclosporine [33,34], TNF-antagonists [35],
Age >40 years 1 plasmapheresis/plasma exchange [36] and cyclophosphamide
Presence of Malignancy/ Haematological [37].
1
malignancy In view of the pharmacogenetic influences underlying great number
Epidermal Detachment >30% 1 of drug reactions like HLA-B 1502 being associated with SJS/TEN
Heart rate >120/min 1 induced by CBZ, PHT, and LTG [38]. HLA-B 5801 with allopurinol
Bicarbonate < 20mmol/L 1 induced SCARs [39] and HLA-B 5701 with abacavir hypersensitivity
[40]. It is also suggested that ethnicity has a role to play in difference of
Urea > 10mmol/L 1
the individual genetic susceptibility [41]. A pharmacogenomic study
Glycaemia >14mmol/L 1
done on CBZ has shown a strong association of HLA-A-3101 and
SCORTEN Probability of death(%)
CBZ- hypersensitivity in Caucasian patients [42]. This association
0-1 3 encompasses all forms of cutaneous eruptions besides SJS/TEN.
2 12 This is in contrary to association of HLA-B 1502 which is specific
3 35 for SJS/TEN in Chinese patients. The association with HLA-A 3101
and CBZ hypersensitivity has been replicated in Japanase [43],
4 58
South Korean [44] and Canadian populations [45].
≥5 90
More recently, drug labels of various drugs have been altered by
[Table/Fig-1]: SCORTEN: A Prognostic scoring system for patients with epidermal
necrolysis the US Food and Drug Administration (FDA) and by the European

2 Journal of Clinical and Diagnostic Research. 2016 Jan, Vol-10(1): FC01-FC04

www.jcdr.net Samina Farhat et al., Antecedent Drug Exposure and Management in SJS and TEN

Cutaneous
S.No Age/Sex Drug Therapy Dose Indications Days to onset Concomitant drugs
manifestation

Quetiapine SR 200mg
12.5mg/day Initially
Seizures with Sodium valproate (600mg/day)
1 35/F Lamotrigine (LTG) Followed by 25mg/day, 20 SJS
BPAD Etizolam (1mg/day)
Then 50mg/day
Propanolol (40mg/day)
Metoprolol SR 100mg/day
Clonidipine 10mg/day
25mg/day for week Olmesartan 20mg/day
2 58/F LTG Then 50mg/day second week BPAD 15 Rosuvastatin 5mg/day SJS
Increased to 100mg/day Quetiapine 25mg/day
Clopidogril 75mg/day Aspirin 75mg/
day
BPAD with Paroxetine
3 30/F LTG 25mg/day, 15 TEN
depression Clonezepam 12.5mg/day
Trigeminal
4 30/F CBZ 200mg/day, 10 Naproxen -500mg/day TEN
Neuralgia
Gabapentin 400mg/day
OLE Nortryptiline 10mg/day
5 60/M PHT 300mg/day post traumatic 10 Citicoline 500mg/day SJS
epilepsy Piracetam 400mg/day
Vit B complex
Ankylosing
6 26/M NSAID NA 15 Thiocholchicoside 8mg/day SJS
spondylitis
7 50/F Levofloxacin 750mg/day UTI 10 None TEN
8 60/F Piroxicam 40mg, i/m stat LBA 2 None SJS
1200mg/day
9 27/F Ibuprofen Osteoarthritis 4 Paracetamol 1000mg/day SJS
For 2-3days
500mg/day i.v infusion
Followed by Levofloxacin 500mg/
10 24/F Levofloxacin RTI 7 None TEN
day
Cefpodoxime 400mg/dayfor 5days
11 50/F Piroxicam 40mg, i/m stat LBA 2 None SJS
Sulfasalazine Aceclofenac 100mg/day
Rheumatoid 1
12 35/F (delayed release 1000mg/day for month Thiocholchicoside 4mg/day SJS
arthiritis month
form)
Valproate 1200mg/day
Initially 50mg/day increased within
13 54/F LTG GTCS 28 Levothroxine 50mcg/day TEN
week to 100mg/day

Initially CBZ CR 400mg/day CBZ CR

14 20/F CBZ GTCS 2 months None TEN
600mg /day
Initially PHT 250mg/day for 1 month
Then CBZ-SR 200mg/day for 3days
15 17/F CBZ/PHT followed by CBZ SR 600mg/day then GTCS 2 months None TEN
PHT 200mg/day

AKT-4
R-450/mg /day
Z-1500mg/day
16 22/F PHT PHT 300mg/day Focal epilepsy 1 month SJS
E 800mg/day
H-300mg/day

[Table/Fig-2]: Characteristic of 16 cases of SJS/TEN with different drug therapies

LTG: Lamotrigine, BPAD: Bipolar affective disorder, CBZ: Carbamazepine, PHT: Phenytoin, OLE: Occipital lobe epilepsy NSAID: non steroidal anti-inflammatory drug, UTI:
urinary tract infection. RTI: respiratory tract infection, LBA: low back ache, FDE:fixed dose eruption. R: rifampin, Z: pyrazinamide, E: Ethmabutol, H:Isoniazid, CR: continous
release, NA: not available

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PARTICULARS OF CONTRIBUTORS:
1. Associate Professor and Head, Department of Pharmacology, Government Medical College (GMC), Srinagar, India.
2. Lecturer, Department of Pharmacology, Government Medical College (GMC), Srinagar, India.
3. Professor and Head, Department of Dermatology, Government Medical College (GMC), Srinagar, India.

NAME, ADDRESS, E-MAIL ID OF THE CORRESPONDING AUTHOR:

Dr. Muddasir Banday,
Lecturer, Department of Pharmacology, Government Medical College, Srinagar-190001, India. Date of Submission: Aug 22, 2015
E-mail : [email protected] Date of Peer Review: Sep 27, 2015
Date of Acceptance: Nov 05, 2015
Financial OR OTHER COMPETING INTERESTS: None. Date of Publishing: Jan 01, 2016

4 Journal of Clinical and Diagnostic Research. 2016 Jan, Vol-10(1): FC01-FC04

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