Dermatological Adverse Drug Reactions in a Tertiary Care Teaching Hospital of Punjab, India—A Pharmacovigilance Study

INTRODUCTION

As per WHO, the definition of pharmacovigilance is “The Pharmacological science relating to the detection, assessment, understanding and prevention of adverse effects, particularly long term and short term side effects of medicines”.¹ The meaning of pharmacovigilance differs from the meaning of “side effect,” as associated effects can be beneficial to some patients, where these effects can be used as therapeutic agents.² Pharmacovigilance or ADR monitoring, launched by WHO in the 1960s in the wake of “thalidomide” disaster, is currently an integrated global effort of more than 70 countries worldwide. After the “thalidomide tragedy”, many countries have established drug-monitoring systems for early detection and prevention of possible drug-related morbidity and mortality. The use of traditional and complementary drugs (e.g., herbal remedies) may also pose specific toxicological problems, when used alone or in combination with other drugs.³ An ACDR due to a drug is any undesirable change in the skin, its appendages, or mucous membranes. Drug eruptions are among the most common cutaneous disorders encountered by dermatologists.^4,5 In fact, monitoring of ADRs is now mandated by regulatory agencies in India. central drugs standard control organization (CDSCO) has mandated all medical institutions to report ADRs originating from their hospitals. The CDSCO is under the Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India. It is the National Regulatory Authority (NRA) of India, and its headquarter is located at FDA Bhawan, Kotla Road, New Delhi. It has 6 zonal offices, 4 sub-zonal offices, 13 port offices, and 7 laboratories spread across the country. There is a wide spectrum of ACDRs seen in the Department of Dermatology, varying from transient maculopapular rash to fatal toxic epidermal necrolysis. The wide and indiscriminate use of drugs has increased the incidence and the modes of presentation of cutaneous drug reactions.⁶ It is the prime responsibility of health care professional (HCPs) to identify potential and actual treatment-related problems, resolve problems, and prevent the future onset of problems due to drug administration. HCPs are encouraged by various regulatory agencies to take responsibility in ADR monitoring and reporting programs. Due to this reason, regulatory agencies regularly disseminate the information regarding ADRs to the general public as well as to HCPs. This would increase awareness about ADRs, motivate the reporting people, benefit medical professionals in drug selection, and enhance better prescription for patients with better patient outcome.⁷ However, underreporting of ADRs is observed among Indian clinicians due to inadequate training on the use of drugs and patient safety monitoring, resulting in humanistic and economic burden to the patients as well as to the society.⁸ ADR reporting helps in drug monitoring and may even guide clinicians, pharmaceutical companies, and regulatory authorities in better drug usage. Thus, ADR monitoring and reporting are important, while prescribing drugs to the patients. Many a times, ADRs are relatively mild and disappear when the drug is stopped or there is reduction in dose, but some of the side effects are serious and last longer. So, it can be concluded that ADRs increase morbidity and mortality of the patients as well as add up to the financial cost to the patients. However, some ADRs are predictable in nature and, hence, with the knowledge of these ADRs, patients can be circumvented from such deleterious effects of the drug treatment, such as in patients with a known allergy or with comorbidities.

MATERIALS AND METHODS

This was a retrospective, observational, noninterventional, cross-sectional study carried out at the Department of Pharmacology and Department of Dermatology at the tertiary care teaching hospital in Amritsar, which is a 1,000 bedded multispecialty hospital. This study was conducted on patients presenting with dermatological reactions due to medications at the Department of Dermatology at SGRDIMSAR, Amritsar from the month of June 2015 to May 2018. The study was approved by the Institutional Ethics Committee. The inclusion criteria of the study were patients of all age groups, both genders, presenting in outpatient department (OPD)/indoor patient department (IPD) of dermatology, patients with any disease and comorbid condition, and patients hospitalized due to dermatological ADR or referred to the OPD of the dermatological department. However, pregnant women, nursing mothers, and patients having any of the chronic illness like chronic renal failure/liver disease were excluded. The demographic data of the patients like patient initial, hospital number, age, sex, marital status, medical history, medication history, past drug allergies, and herbal and cosmetic use were recorded on the case record form provided by CDSCO. In addition, the prescription given to the patient including the drugs prescribed with dose, frequency, and duration of the treatment was noted on this case record form. Diagnosis of ACDRs was done by dermatologists and the assessment of the probability of the reactions was done in the pharmacovigilance cell, Department of Pharmacology. All the doctors, residents, interns, and students were encouraged to notify any suspected ACDRs by either telephonic or direct reporting to the pharmacovigilance cell, Department of Pharmacology. Reporting was done according to “CDSCO ADR Reporting Form”.⁹ On the basis of collected data, the incidence rate was calculated and the ACDRs were classified on the basis of age, sex, and the most common drug causing them.

CAUSALITY ASSESSMENT

The ADR algorithm and the causality assessment scale were also included in the data entry format. The patients and offending drugs were identified through the history of medications taken, prescription monitoring, and reports obtained from the HCPs (nurses, doctors, etc.). Data were collected from patient’s case sheet and transferred to data entry format for evaluation. The collected data were analyzed by using the Naranjo causality assessment scale (Table 1),¹⁰ WHO probability assessment scales (Table 2),¹¹ and Hartwig and Siegel severity assessment scale (Table 3).¹² The collected data were further analyzed for their appropriateness and suitability, and the interpretation was made for the collected data. The suspected ADRs were reported to the regional pharmacovigilance center and the peripheral center. Causality assessment was done by the WHO causality assessment scale, classifying ADRs into certain, probable, possible, unlikely, unclassified, and inaccessible. ACDRs reported under certain, probable, and possible were included in the study. Severity assessment was done by the modified Hartwig and Siegel scale,¹² which classifies the severity of ADRs as mild, moderate, or severe based on factors like the necessity of change in treatment, increased duration of hospital stay, and disability produced by ADRs. Patients presenting difficulties in communication, mental illness, and accidental or intentional poisoning due to drugs were excluded from the study. Preventability of ADRs was evaluated by Schumock and Thornton’s criteria (Table 4).¹³ The data obtained were collected, compared, and reviewed, calculating the percentage to assess their significance and evaluation.

RESULTS

The result of this study on 152 patients attending Dermatology OPD/IPD reported with ADRs is presented in Tables 5 to 8. Sex-wise distribution is given in Table 5. From Table 5, it can be analyzed that the most common incidence (54%) was reported in the age group of 18 to 35 years and the higher incidence rate was observed in males as compared to females (M:F = 1:0.52). The most common age group presenting with ACDRs was 18 to 35 years with 54% having ACDRs, while in the age group of 63 to 80 years, the percentage of ACDRs was least (4%). Out of 152 ACDRs reported in this retrospective study, the most common was urticaria (30.2%) followed by fixed drug eruptions (16.4%). Other reported ACDRs were angioedema (9.0%), erythema multiforme (10.5%), Steven–Johnson syndrome (SJS) (9%), acneiform/follicular eruption (5.9%), toxic epidermolytic necrosis (2.6%), exfoliative dermatitis (2.6%), photosensitivity drug eruption (3.9%), hypersensitivity syndrome (3.2%), serum sickness (1.3%), vasculitis (1.3%), and others (0.6%). As is evident from Table 6, the most common drugs responsible for ACDRs in this prospective study were NSAIDs and fluoroquinolones followed by systemic steroids, oral contraceptive pills, ampicillin, ACE inhibitors, and so on. According to WHO causality assessment, 19/52 cases were certain (13.0%), 85/152 were probable (56.1%), and 47/152 were possible (30.7%) in nature. On severity assessment by the modified Hartwig and Siegel scale, 110/152 (72.3%) ACDRs were mild, 38/152 (25%) were moderate, and 4/152 (2.05%) cases were of severe type. Preventability assessment by the modified Schumock and Thornton scale¹³ revealed that 105/152 ACDRs (69.1%) were definitely probable, 26/152 (20.51%) were probably preventable, and 21/152 (13.8%) were not preventable.

DISCUSSION

Drugs are used for the treatment and prophylaxis of various disease conditions and are considered as safe when used rationally. Drugs show some ADRs in various patients. ADR monitoring is an essential aspect of therapeutics. However, most of the time, it is overlooked and not considered important. Even when observed, many would not document and report voluntarily. Establishing pharmacovigilance units in hospitals has facilitated this activity to a great extent. This study focused on the pattern of dermatological ADRs of drug class in the post-marketing surveillance studies to find out the effects in a large and diverse population. This study was carried out with an approach to reveal the pattern of ACDRs with simultaneous vision of establishing the impact of pharmacovigilance activity in our tertiary care center. In a study conducted by Chatterjee et al.,¹⁴ it was concluded that the incidence of the drug-induced adverse skin reaction was found to be 2 to 6% at the dermatology outpatient setting. The present study has revealed that higher numbers of ADRs were reported in males. Similar results were seen in other studies showing higher male preponderance; however, a female preponderance was seen in other studies as well.¹⁵ The reason for higher incidence in the present study could be that males are more aware and are more mobile and, hence, have access to treatment before ADRs become severe. In the present study, the most suspected ADRs were urticaria (46%) cases, followed by fixed drug eruptions (16.4%), angioedema (9%), acne (5.9%), and SJS (5.9%), followed by toxic epidermal necrolysis, swelling of lips, and others. Highly occurring ADR in the present study was urticarial rash, which is similar to results obtained in other studies.¹⁶ There were studies conducted in the past,¹⁷ which showed that the most common suspected ADR was rash followed by urticaria and/or fixed drug eruptions (FDE), which were also observed in the present study, and microbial agents, NSAIDs, corticosteroids, and antiepileptics. Chatterjee et al.¹⁴ showed the same higher incidence of the suspected drug classes, which were antimicrobial agents, antiepileptics, and NSAIDs. This is quite consistent with the present study in which the most offended drug classes were NSAIDs, corticosteroids, hormonal preparations, etc. In a study by Suthar et al.,¹⁸ NSAIDs, antibiotics, and antiepileptics were reported to produce a higher incidence rate, in which the development of ADRs in two-thirds of the patients was due to NSAIDs and antibiotics. In our study, 4 (2.4%) cases of toxic epidermal necrosis (TEN) and 15 (9%) cases of SJS were reported. In a study conducted by Lihite et al.,¹⁹ 2 cases of TEN and 1 case of SJS were reported out of 108 cases over a period of 5 months, whereas Sushma et al.²¹ have shown 11.4% fatal cases of TEN and SJS. However, Sharma et al.²⁰ reported that there is a change in cutaneous ADR patterns and the possible reason for this change can be attributed to the emergence of newer drugs/molecules and changing trends in the prescribing pattern of drugs by clinicians. In the present study, most of the ADRs in our study were designated as possible (30.7%) or probable (56.1%) and 13% as certain as per WHO-UMC (Uppsala Monitoring Centre) causality assessment. These findings are consistent with a study conducted by Sushma et al.²¹ showing the similar effects in patients. Among them, possible ADRs were highly observed. A study by Suthar et al. have shown that commonly incriminated drugs causing CADR (cutaneous adverse drug reaction) were antimicrobial agents i.e. ciprofloxacin (21.57%) followed by phenytoin (9.8%), diclofenac sodium (6.86%), anti-snake venom (6.86%) and vancomycin (3.92%), respectively.¹⁸ The percentage of dermatological ADRs falling in the category of definitely preventable is very high (69.1%), probably preventable (17.1%), and not preventable (13.8%) (Table 8). According to United States-Food and Drug Administration (US-FDA) criteria,²² any adverse reaction is denoted as serious when the patient outcome falls within categories, such as death, life-threatening, hospitalization (initial or prolonged), disability or permanent damage, congenital or birth defect, or required intervention to prevent permanent damage to patient. However, in our study, causality assessment revealed that 13.0% cases were certain, 56.1% were probable, and 30.7% were possible, which were comparable to those reported by Chatterjee et al.¹⁴ Analysis of the results showed that in this prospective study, NSAIDs and fluoroquinolones were the most common drugs responsible for FDE. Other studies²³ have documented sulfonamides and tetracycline as the most common causative agents. Hartwig severity assessment showed that 04/152 (2.6%) of the total reported ACDRs were severe, 38/152 (25%) cases were moderate, and 110/152 (72.3%) cases were mild. Similarly, from Table 8 of the present study, it can be concluded that 105/152 (69.1%), 26/152(17%), and 21/152 (13.8%) of ACDRs were definitively preventable, probably preventable, and not preventable, respectively, as has been evaluated by the modified Schumock and Thornton scale. Polypharmacy is a recognized risk factor for ADRs particularly in the elderly and is likely to increase the incidence of ADRs, since therapeutic guidelines indicate that multiple therapies are used to treat various diseases.²⁴ Similarly, patients with multiple diseases and patients with impaired hepatic or renal status are at an increased risk of developing ADRs due to the use of multiple drugs for their multiple diseases. In an Indian study conducted by Jose et al.,²⁵ polypharmacy and the multiple disease state (52.9%) were revealed as the most prevalent predisposing factors for the development of ADRs (93.1 and 52.9%, respectively). Another Indian study by Sriram et al.²⁶ showed that multiple drug therapies (68%), advanced age (56%), and comorbid diseases (42%) were the major risk factors for developing ADRs.

CONCLUSION

Urticaria, fixed drug eruption, and acneiform eruption are the most commonly encountered ACDRs at our tertiary care center. The most common drugs responsible were NSAIDs, fluoroquinolones, corticosteroids, isoniazid, rifampicin, metronidazole, and antimalarial drugs. Polypharmacy and allergy are important risk factors, which can be prevented by taking proper history, prescribing alternative drugs, and educating the patients about the risk of self-medication. There are gaps between knowledge and ADR reporting among doctors working in hospitals, which need to be addressed by improved training in pharmacovigilance and risk perceptions of drugs.

REFERENCES

1. International monitoing of adverse reactions to drugs. WHO Adverse Reaction Terminology,Uppsala: The Uppsala Monitoring Centre, 2007.

2. Rawlins MD, Thompson JW. Pathogenesis of adverse drug reactions. ed. DM, Davies ed. In: Textbook of adverse drug reactions. Oxford: Oxford University Press, 1977; p.10

3. Rabbur RSM, Emmerton L. An introduction to adverse drug reaction reporting system in different countries. Int J Pharm Prac 2005;13(1):91-100.

4. Neupane S, Sharma S. Cutaneous adverse drug reactions. J Clin Diagn Res 2012;6:445-448.

5. Mahboob A, Harron T. Drugs causing fixed eruptions: a study of 450 cases. Int J Dermatol 1998;37:833-838.

6. Bilimoria FE, Shah BE,Drug reactions. In: Valia RG, Valia RR. IAVDL Textbook of Dermatology.India: Blalani Publication; 2008; pp.1633-1668.

7. American Society of Health-System Pharmacists, ASHP guidelines on adverse drug reaction monitoring and reporting. Am J Health-Syst Pharm 1995;52:4179.

8. Kumarasamy N, Solomon S, Erica Peters R, et al. The use of antiretroviral drugs in the treatment of people living with human immunodeficiency virus: experience in a south Indian tertiary referral centre. J Assoc Physicians India 2000;48:390-393.

9. Central drugs standard control organization. Suspected adverse drug reaction reporting form; 2010 [Cited in 2018]. Available fromhttp://www.cdsco.nic.in/ADR_form_pvpi.pdf

10. Naranjo CA, Busto U, Sellars EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-245.

11. The use of the WHO-UMC system for standardised case causality assessment. Accessed from:https://www.who.int/medicines/areas/quality_safety/safety_efficacy/WHOcausality_assessment.pdf(last accessed on 17-12-2018)

12. Hartwig SC, Siegel J, Schneider PJ. Preventability and severity assessment in reporting adverse drug reactions. Am J Hosp Pharm 1992;49:2229-2232.

13. Schumock GT, Thornton JP. Focusing on the Preventability of Adverse Drug Reactions. Hosp Pharm 1992;27:538.

14. Chatterjee S, Ghosh AP, Barbhuiya J, et al. Adverse cutaneous drug reactions: a one year survey at a dermatology outpatient clinic of a tertiary care hospital. Indian J Pharmacol 2006;38:429-231.

15. Sudershan V, Siddiqua S, Aruna D, et al. Cutaneous adverse drug reactions in a tertiary care hospital. Pharm Lett 2011;3(6):210-217.

16. Ghosh S, Acharya L, Rao P. Study and evaluation of various cutaneous adverse drug reactions in kasturba hospital, Manipal. Indian J Pharm Sci 2006;68(2):212-215.

17. Anjaneyan G, Gupta R, Vora R. Clinical study of adverse cutaneous drug reactions at a rural based tertiary care centre in Gujarat. Natl J Physiol Pharm Pharmacol 2013;3(2):129-136.

18. Suthar J, Desai S. A study of Adverse Cutaneous Drug Reactions in Outdoor Patients attending to Skin and V. D. Department of Shree Krishna Hospital, Karamsad. Int J Res Pharm Biomed Sci 2011;2(1):274-279.

19. Lihite RJ, Lahkar M. A Study on Cutaneous Adverse Drug Reactions in ADR Monitoring Centre of Tertiary Care Hospital, Guwahati. J Appl Pharm Sci 2013;3(03):78-81.

20. Sharma VK, Sethuraman G, Kumar B. Cutaneous adverse drug reactions: Clinical pattern and causative agents- a 6 year series from Chandigarh. Indian J Postgrad Med 2001;47:95-99.

21. Sushma M, Noel MV, Ritika MC, et al. Cutaneous adverse drug reactions: a 9-year study from a South Indian Hospital. Pharmacoepidemiol Drug Saf 2005;14(8):567-570.

22. MedWatch: The FDA Safety Information and Adverse Event Reporting Program.http://www.fda.gov/Safety/MedWatch/.HowToReport/ucm053087.htm(date of access: 25th December, 2018)

23. Mahboob A, Harron T. Drugs causing fixed eruptions: a study of 450 cases. Int J Dermatol 1998;37:833-838.

24. Davies EC, Green CF, Mottram DR. Adverse Drug Reactions in Hospitals: A Narrative Review. Curr Drug Saf 2007;2:79-87.

25. Jose J, Rao PGM. Pattern of adverse drug reactions notified by spontaneous reporting in an Indian tertiary care teaching hospital. Pharmacol Res 2006;54:226-233.

26. Sriram S, Ghasemi A, Ramasamy R. Prevalence of adverse drug reactions at a private tertiary care hospital in south India. J Res Med Sci 2011;16(1):16-25.