Evaluation of Dermatological Adverse Drug Reactions in a Tertiary Care Hospital of Northern India

 

Sumit Kumar¹, Badruddeen²*, S. P. Singh¹, Akhtar Juber², Mohammad Irfan Khan²

¹Department of Pharmacology and Therapeutics, GSVM Medical College, Kanpur (U.P), India.

²Faculty of Pharmacy, Integral University, Lucknow (U.P), India.

 

ABSTRACT:

In clinical practice dermatological reactions are common but comprehensive information regarding their incidence, severity is often not available as many cases go unreported.  The objective of this study was to evaluate the types of dermatological adverse drug reactions (ADRs) in a tertiary care hospital and determine their causal relationship with the offending drug. This prospective, observational study was conducted at GSVM medical college Kanpur, Northern India for one year. Patients of all age and either sex were included. Dermatological adverse drug reactions were reported by the physicians of various department of the hospital and their causality assessments were performed as per World health organization (WHO) Uppsala monitoring centre (UMC), Expanded Rawlins and Thompson’s classification was used for determining type of ADRs, outcome and seriousness of ADR were assessed as per WHO. Descriptive statistics were used for data analysis. A total of 105 dermatological adverse drug reactions were reported from various departments of this tertiary care hospital. Most of the adverse drug reactions were observed in the age group of 0–20 year. Rash (35 ADRs) was commonly reported reaction. Anticancer drugs lead to 48 ADRs (mainly with Paclitaxel+Carboplatin-11, Adriamycin+Cyclophosphamide-7), followed by Antibacterial with 28 ADRs (mainly with Vancomycin-6, Cefixime-4 and Amoxicillin-4). A total of 8 ADRs were of serious type mainly with Vancomycin-Red man syndrome-6, Carbamazepine-toxic epidermal necrolysis-1 and Nimesulide-Steven Johnson Syndrome-1. Most of the adverse drug reactions on causality assessment were possible (77, 73.33%) and Probable (28, 26.67%) in nature. Type -B ADRs account for 2/3^rd of the total dermatological ADRs. It’s highly emphasized for careful monitoring for ADRs associated with high risk drugs and more awareness should be created.

 

 

 

INTRODUCTION:

In clinical practice every physician comes across many instances of suspected dermatological adverse drug reactions in different forms. As such dermatological reactions are common but comprehensive information regarding their incidence, severity is often not available as many cases go unreported.

 

An adverse drug reaction (ADR) is any noxious, unintended, and undesired effect of a drug that occurs at doses used for prophylaxis, diagnosis, or therapy or for modification of physiological function^[1].

 

There are different types of adverse drug reaction related to skin. ADRs may lead to transitory or permanent organ damage, including death. The skin is the largest organ in the body and skin reactions due to drug exposure are a common problem. Any medicine can induce dermatological reactions and certain drug classes, such as non-steroidal anti-inflammatory drugs, antibiotics and antiepileptic, have drug eruption rates approaching 1%–5%^[2]. In India epidemiological studies estimated that ADRs are fourth to sixth leading cause of death^[3]. Dermatological adverse drug reactions are among the most frequent adverse drug events, approximately 2.9%-5.6% of the hospital admissions are due to ADR and 35% of the hospitalized patients experience at least one ADR during their stay in the hospital^[4]. Dermatological drug reactions may be caused by several different mechanisms, but in most of the cases the exact mechanism is unidentified. Many drug eruptions are the resultant of a hypersensitivity reaction with an implicit immune mechanism. Skin (dermatological) reactions as a result of non-immunological causes are more common and include cumulative toxicity, overdose, photosensitivity, drug interactions and metabolic alterations.

 

MATERIAL AND METHOD:

A prospective, observational, non-interventional study carried out at in-Patient and out-Patient setting in various depart­ment of GSVM medical college Kanpur U.P for a period of one year (Jan 2016-dec 2016). ADRs were mainly reported from outpatient departments as well as from wards of cardiology, dermatology, gynecology, medicine, ophthalmology, paediatric, psychiatry, T.B and chest, Oncology and neurology. Permission from Institutional Ethical Committee was obtained prior to the initiation of this study.

 

Inclusion criteria’s:

·       Patients of all age groups and either sex.

·       All the suspected ADRs that may be due to the medications, both prescribed and over the counter, taken by patients either as inpatients or outpatients.

 

Exclusion Criteria’s:

·       Patients who could not recall the name of the suspect medicines consumed.

·       Patients who were mentally retarded and unconscious.

·       Patients who consumed alternative system of medicine.

·       Patients who developed ADRs due to intentional or accidental poisoning, ADRs due to the fresh blood/ blood products, patients with drug abuse and intoxication.

 

Patient demographic data like patient initial, OPD/IPD number, age, sex, medical history, medication history, surgery history, allergies, management and outcome of ADR had been recorded on the Suspected ADRs reporting form of Indian Pharmacopoeia commission. Causality of ADRs was evaluated by WHO-UMC assessment scale, outcome and seriousness of ADR as per WHO and type of ADR using Expanded Rawlins and Thompson’s classification. Descriptive statistics were used for data analysis.

 

RESULTS:

The most common age group having maximum number of ADRs was 0-20 year followed by age group 40-60 year (Table 1). Female population has more number of ADRs (65.72%) followed by male patients (34.28%). A total of 105 ADRs and 12 different kinds of ADRs were associated with dermatological system (Table 2), among which most common was rash  (33.33%) followed by alopecia (20.95%), pigmentation (11.43%), swelling (11.43 %), mucositis (8.58%), Itching(7.63%). Most of the ADRs belongs to non-serious category, account 92.39 % and serious ADRs account only 7.61 % of total dermatological ADRs (Figure 1). Twelve different types of ADRs were visible in dermatological system (Figure 2) among which are rash (35), Alopecia (22), Pigmentation (12), Swelling (12), Mucositis (9), Itching (8), 2 case of exfoliative dermatitis, single case each of TEN, Steven Johnson Syndrome (SJS), red induration, Mottling and bullous pemphigoid.

 

Table 1: Distribution of dermatological-ADRs on the basis of patient age and sex.

Age (Yrs)	No. of  Patient		(N)		No. of  ADRs		( n )
	Female	Male	Total	%	Female	Male	Total	%
0-20	13	19	32	38.55	17	21	38	36.20
20-40	19	2	21	25.30	26	2	28	26.66
40-60	14	9	23	27.72	20	10	30	28.57
>60	4	3	7	8.43	6	3	9	8.57
	50	33	83		69	36	105
	60.24	39.76			65.72	34.28		%

 

 

 

 

Figure 1: Seriousness of dermatological ADRs as per WHO

 

Figure 3: Serious ADRs along with culprit drug

 

Figure 4: Causality of dermatological ADRs

 

As per WHO causality assessment most of ADRs belongs to possible type (73.33%) followed by probable type (26.67%). 92.39 % ADRs are of non serious nature followed by 7.61 % ADRs of serious nature. Most (61.90% ) of ADRs recovered while 37.15% ADRs not recovered and outcome of only single ADR is not known. Most ADRs are of type-B (66.66%), followed by Type-C (31.43%) and Type-A  (1.90%) as per Expanded Rawlins and Thompson’s classification (Table 3). Out of total 8 serious ADRs, 6 dermatological ADRs (Red man syndrome) belong to Vancomycin, 1 ADR Toxic epidermal necrolysis (TEN) belong to Carbamazepine and 1 ADR (SJS) belong to Nimesulide (Figure 3).

 

On WHO causality parameter- 73.33 % ADRs were of possible type and rest belongs to probable (26.67%) category (Figure 4).

 

Table 2: Various types of dermatological adverse  drug reactions.

S. No	Types  of Skin Reaction	No.of ADR (n=105)	% of ADRs
1.	Rash	35	33.33
2	Alopecia	22	20.95
3.	Pigmentation	12	11.43
4.	Swelling	12	11.43
5.	Mucositis	9	8.58
6.	Itching	8	7.63
7.	Exfoliative dermatitis	2	1.90
8.	TEN	1	0.95
9.	SJS	1	0.95
10.	Red induration	1	0.95
11.	Mottling	1	0.95
12.	Bullous pemphigoid	1	0.95

 

 

Figure 2 :Different types of dermatological ADRs.

Table 3: Assessment of dermatological ADRs

Causality as per WHO	No. of ADRs (n=105)	% of ADRs
Possible	77	73.33
Probable	28	26.67
Seriousness - WHO
Serious	8	7.61
Non-serious	97	92.39
Outcome of Reaction-WHO
Recovered	65	61.90
Not recovered	39	37.15
Unknown	1	0.95
Type Of ADRs
A	2	1.90
B	70	66.66
C	33	31.43

 

 

Figure 5: Class of drug  associated with Dermatological ADRs.

 

Most of Dermatological ADRs were associated with Anticancer drugs (45.72%) followed by antibacterial drugs (26.66%), NSAIDs (8.58%), Antiepileptic drugs (3.82%), Haematinics (2.86%), Vaccines  (2.86%), antidiabetics  (1.9%),  antiviral drugs (1.9%)  and  0.95 % ADRs each with antiamoebic drugs, antiulcer drugs, anthelminthics, anticoagulants, antiplatelets  and antivenoums (Figure 5).

 

Table 4: Suspected drugs with associated dermatological adverse drug reactions.

S. No	Drug	ADRs	No. of ADRs
	Antibacterials
1.	Vancomycin	Rash (red man syndrome)-6	6
2.	Rifampicin	Skin pigmentation-2	2
3.	Amoxicillin	Generalized rash-3, Itching-1	4
4.	Cefixime	Rash-2, Swelling-2	4
5.	Ceftriaxone	Rash-2, Itching-1	3
6.	Piperacillin	Exfoliative dermatitis-1, Rash-1	2
7.	Amikacin	Parotid swelling-1	1
8.	Meropenem	Rash-1	1
9.	Levofloxacin	Rash-1, Leg Swelling -1, Mottling-1	3
10.	Linezolid	Mottling-1	1
11.	Ciprofloxacin	Itching-1	1
	NSAIDs
12.	Ibuprofen	Black pigmentation lips-1, Rash-4,m ucositis-1	6
13.	Paracetamol	Rash-1	1
14.	Tramadol	Swelling (angioedema)-1	1
15.	Nimesulide	SJS-1	1
	Anthelminthics
16.	Albendazole	Generalized Swelling-1	1
	Antivirals
17.	Efavirenz	Rash-1	1
18.	Nevirapine	Rash-1	1
	Antiepileptics
19.	Carbamazepine	TEN-1, Red induration-1, Swelling-1, Mucositis-1	4
	Vaccines
20.	DPT vaccine	Leg Swelling-1, Eye swelling-1, Rash-1	3
	Antiplatelets
21.	Clopidogrel	Rash-1	1
	Anticoagulants
22.	Heparin	Rash-1	1
	Antiulcer
23.	Magaldrate	Rash-1	1
	Antidiabetics
24.	Metformin+ Indapamide	Bullous pemphigoid-1, Itching-1	2
	Antivenoum
25.	Antisnake venoum	Rash-1	1
	Anticancer
26.	Cisplatin+ Adriamycin	Alopecia-1, Pigmentation nail-1	2
27.	Cisplatin+5-FU	Rash-1, Alopecia-2	3
28.	Paclitaxel	Mucositis-1, Pigmentation Nail-1,Alopecia-1	3
29.	Paclitaxel+Carboplatin	Alopecia-8, Itching-1 Pedal Odema-1, Pigmentation Nail, skin-1	11
30.	Adriamycin+ Cyclophosphamide	Pigmentation nail and skin-3, Alopecia-4	7
31.	Adriamycin+5-FU	Pigmentation-1, Alopecia-1	2
32.	Ifosfamide+ Carboplatin	Mucositis-1, Alopecia-1	2
33.	Cyclophosphamide+5-FU	Alopecia-1, Mucositis-1	2
34.	Ifosfamide+ Adriamycin	Mucositis-1	1
35.	Paclitaxel+ Adriamycin	Mucositis-1, Pigmentation nail-1, Alopecia-1	3
36.	5-FU	Alopecia-1	1
37.	Cyclophosphamide+ Docetaxel	Mucositis-1, Alopecia-1, Rash-1	3
38.	Cyclophosphamide+ Epirubicin	Pigmentation skin, nail-1, Rash-1	2
39.	Rituximab	Swelling face-1	1
40.	Cisplatin	Alopecia-1, Pigmentation nail-1	2
41.	Imatinib	Swelling face-1, Mucositis-1, Exfoliative dermatitis-1	3
	Haematinics
42.	Iron+ folic acid+ vit B-12	Rash-1, Itching-2	3
	Antiamoebics
43.	Dicyclomine	Rash-1	1

 

 

Figure 6: Drugs associated with dermatological ADRs.

 

The Paclitaxel+Carboplatin was associated with 11-dermatological ADRs, followed by  7-ADRs with Cyclophosphamide+Adriamycin, 6-ADRs with Vancomycin,  6-ADRs with Ibuprofen  and  4-ADRs each with Amoxicillin, Cefixime and Carbamazepine (Figure6). The suspected drugs with associated dermatological adverse drug reactions are tabulated as in Table 4.

 

DISCUSSION:

In our study 105 ADRs are suspected with different offending drugs of which majority of ADRs were reported from female patients than from male. Studies conducted by Sudershan et.al, Chatterjee et.al, Suthar et.al,  Nandha et.al and  Mbuagbaw et.al  has showed  female preponder­ance^[5,6,7,8,9]. The Reason may be due to more concern of female towards their skin and hence dermatological ADRs maximally reported by female, while studies conducted by Shah et.al, Sharma et.al,  Sushma et.al,  Pudukadan et.al and Dimple et.al showed male preponder­ance^{[10,11,12,13,14]}.

 

In present study, the most suspected ADRs were Rash (33.33%) followed by Alopecia (20.95%), pigmentation (11.43%), swelling ( 11.43 % ), mucositis (8.58%), itching (7.63%). Highly occur­ring ADR in our study was rashes, which are similar to results obtained in studies of  Ghosh et.al and  Dubeyet.al ^[15,16].

 

The study showed 97 non-serious and 8 serious dermatological ADRs i.e maximum ADRs are of non-serious type, which was similar to studies conducted by Shah et.al and Dimple et.al.

 

In our study among various age group  associated with more dermatological ADRs was 0-20 years followed by 40-60 years of age, which is contrary to the study conducted by Monalis et.al^[17] that Showed 41-50 year group, Chawlaet.al ^[18] showed mean age of patients who experienced ADRs was 32 year and in  Sudershan et.al study -age group between 21-30 years developed more dermatological ADRs.

 

The most common offending drug classes were anti­cancer drugs 48 ADRs (45.72%) followed by 28 (26.66%) antibacterial, 9 (8.58%) were of NSAIDS, 4 ADRs (3.82.%) were of anti-epileptics. It is in contrast to the study conducted by Chatterjee et.al that showed the suspected drug class were antimicrobial agents (34.10%), antiepileptic (32.88%) and NSAIDs (21.51%) and study by Suthar et.al showed NSAIDs, antibiotics and antiepileptics as common offending drug class.

 

In our study, Paclitaxel + Carboplatin (11-ADRs) was highly suspected drug followed by Cyclophosphamide+ Adriamycin (7-ADRs), Vancomycin (6-ADRs), Ibuprofen (6-ADRs), this was in contrast to the study conducted by Dimple, in which paracetamol was highly suspected drug followed by amoxicillin.

 

In our study, one case of toxic epidermal necrolysis (TEN) and one case of Steven Johnson Syndrome (SJS) were reported which is similar to study conducted by Dimple ^[14]. In study conducted by Lihite et.al ^[19] two cases of TEN and one case of SJS were reported whereas Sharma et.al has shown 11.4% fatal cases of TEN and SJS.

 

Most of the ADRs in our study were specified as possible (73.33.%) followed by probable (26.67%) in WHO-UMC causality assessment which is quite con­sistent with studies of Shah et.al possible-69 % and Dimple possible-54.64%, probable-36.08%. However, it is in contrast to the study conducted by Chatterjee et.al -probable -73.2% and Suthar et.al probable -80.35%.

 

CONCLUSION:

It is concluded from our study that female patients encountered more ADRs. As per age groups are concerned more cases were seen in age group of 0-20 years (65.72%). In ADR assessment 2/3^rd of total ADRs were of type-B (66.66%), there was no D, E or F type ADRs. In WHO seriousness assessment, 92% cases were non-serious type. Anticancer drugs were the most common offending drug class with 45.72% cases followed by antibacterial (26.66%) and NSAIDs (8.58%), among anticancer drugs, paclitaxel +carboplatin has leads to higher number of dermatological ADRs. Rash (33%) was the most common reaction observed followed by alopecia (20.95%), pigmentation (11.43%) and swelling (11.43%). On WHO-UMC scale of causality assessment 73.33% were of possible and 26.67% probable type. Common and serious dermatological adverse drug reactions can be avoided by having knowledge of the incidence, clinical pattern and causative agents. The burden of ADRs is resulting into switching or dis­continuation of drug as well as medication non-adher­ence. Due to lack of interest in ADR monitoring and poor response of the physician for ADR monitoring many of them go unreported and chance to find rare and new dermatological ADRs is also gets narrowed. It’s highly emphasized for careful monitoring for ADRs associated with high risk drugs and more awareness should be created in order to decrease the morbidity and mortality which are associated with the use of the drugs, thereby preventing patients from unnecessary suffering that can be prevented if sufficient ADRs profile is substantially known.

 

ACKNOWLEDGEMENT:

Authors are thankful to all the departments of GSVM Medical College Kanpur and faculty of pharmacy Integral University Lucknow for providing suitable facilities and support for the successful completion of this study (IU/R and D/2017-MCN000203).

 

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Received on 08.02.2019         Modified on 07.03.2019

Accepted on 30.03.2019         © RJPT All right reserved