Generic placeholder image

Current Drug Safety

Editor-in-Chief

ISSN (Print): 1574-8863
ISSN (Online): 2212-3911

Research Article

Patient, Disease, and Drug-Related Risk Factors Associated with Phenytoin- Induced Cutaneous Adverse Drug Reactions in South Indian Epileptic Patients - A Prospective Case-Control Study

Author(s): Shobana John, Bhutorn Canyuk, T.C. Vijay Anand, Chonlaphat Sukasem and Sutthiporn Pattharachayakul*

Volume 17, Issue 3, 2022

Published on: 24 January, 2022

Page: [241 - 249] Pages: 9

DOI: 10.2174/157488631602211118122907

Price: $65

Abstract

Background: Phenytoin is the most commonly reported aromatic Anti-Epileptic Drug (AED) to cause Cutaneous Adverse Drug Reactions (CADRs). Cutaneous adverse drug reactions may be immune or non-immune mediated. It has been observed that predisposition is multifactorial and that gene mutations alone cannot be the cause.

Objectives: In this study, we investigated the patient, disease, and drug-related risk factors associated with phenytoin-induced cutaneous adverse drug reactions in South Indian epileptic patients.

Methods: This study was conducted as a single-center prospective case-control study over a period of 13 months. The Fisher’s exact test and multivariate binary logistic regression analysis were used to test the association of single and multiple variables, respectively.

Results: This study comprised 26 patients with phenytoin-induced cutaneous adverse drug reactions (PHT-CARDs) and 32 phenytoin-tolerant controls with a mean age of 40.60±18.15 and 36.21±14.71 years, respectively. Among 26 phenytoin-induced cutaneous adverse drug reactions, 76.92% cases were mild-moderate reactions and 23.07% were severe. The onset latency period of these reactions ranged from 7-42 days. The multivariate analysis showed that multiple AEDs (OR =18.62, 95% CI 4.28-80.87, p=< .001) and comorbidities (OR= 5.98, 95% CI 1.33-26.78, p=.01) are risk factors for PHT-CADRs. PHT-SCARs were shown to be associated with previous allergy history (OR= 31, % CI 2.40-398.8, p=.008).

Conclusion: The risk factors found to be associated with CARDs in South Indian Epileptic patients are multiple AEDs, comorbidities, and past allergic history. Therefore, physicians and other associated health care professionals should closely monitor the patients when phenytoin is employed.

Keywords: Cutaneous Adverse Drug Reactions (CADRs), AEDs, Phenytoin (PHT), risk factors, epileptic patients, gene mutations.

Graphical Abstract
[1]
Valeyrie-Allanore L, Sassolas B, Roujeau JC. Drug-induced skin, nail and hair disorders. Drug Saf 2007; 30(11): 1011-30.
[http://dx.doi.org/10.2165/00002018-200730110-00003] [PMID: 17973540]
[2]
Chatterjee SGA, Barbhuiya J, Dey SK. Adverse cutaneous drug reactions: A one year survey at a dermatology outpatient clinic of a tertiary care hospital. Indian J Pharmacol 2006; 38(6): 429-31.
[http://dx.doi.org/10.4103/0253-7613.28212]
[3]
Patel TK, Barvaliya MJ, Sharma D, Tripathi C. A systematic review of the drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Indian population. Indian J Dermatol Venereol Leprol 2013; 79(3): 389-98.
[http://dx.doi.org/10.4103/0378-6323.110749] [PMID: 23619444]
[4]
Glick TH, Workman TP, Gaufberg SV. Preventing phenytoin intoxication: safer use of a familiar anticonvulsant. J Fam Pract 2004; 53(3): 197-202.
[PMID: 15000924]
[5]
Chandrarathna NPA, Manju V, Adiga US. Drug utilization study in epilepsy in a Tertiary Care Hospital. Biomed Pharmacol J 2019; 12(2)
[http://dx.doi.org/10.13005/bpj/1691]
[6]
Błaszczyk B, Szpringer M, Czuczwar SJ, Lasoń W. Single centre 20 year survey of antiepileptic drug-induced hypersensitivity reactions. Pharmacol Rep 2013; 65(2): 399-409.
[http://dx.doi.org/10.1016/S1734-1140(13)71015-6] [PMID: 23744424]
[7]
Campos-Fernández MdelM, Ponce-De-León-Rosales S, Archer- Dubon C, Orozco-Topete R. Incidence and risk factors for cutaneous adverse drug reactions in an intensive care unit. Rev Invest Clin 2005; 57(6): 770-4.
[PMID: 16708902]
[8]
Pirmohamed M, Kitteringham NR, Park BK. The role of active metabolites in drug toxicity. Drug Saf 1994; 11(2): 114-44.
[http://dx.doi.org/10.2165/00002018-199411020-00006] [PMID: 7945999]
[9]
Patel TK, Thakkar SH, Sharma D. Cutaneous adverse drug reactions in Indian population: A systematic review. Indian Dermatol Online J 2014; 5(Suppl. 2): S76-86.
[http://dx.doi.org/10.4103/2229-5178.146165] [PMID: 25593813]
[10]
Shi YW, Min FL, Zhou D, et al. HLA-A*24:02 as a common risk factor for antiepileptic drug-induced cutaneous adverse reactions. Neurology 2017; 88(23): 2183-91.
[http://dx.doi.org/10.1212/WNL.0000000000004008] [PMID: 28476759]
[11]
Du-Thanh A, Kluger N, Bensalleh H, Guillot B. Drug-induced acneiform eruption. Am J Clin Dermatol 2011; 12(4): 233-45.
[http://dx.doi.org/10.2165/11588900-000000000-00000] [PMID: 21668032]
[12]
Rita V, Nilofar D, Nidhi J, Rochit S. A study of Adverse Cutaneous Drug Reactions (ACDR) owing to antiepileptics at a rural-based tertiary-care center, Gujarat. Natl J Physiol Pharm Pharmacol 2016; 6(2): 140-5.
[http://dx.doi.org/10.5455/njppp.2016.6.0511201597]
[13]
Roji M, Sebastian M, Lucca JM, Pss R. Phenytoin induced oral Lichenoid eruption and melasma: A case report. Indian J Pharm Pr 2018; 11(1): 55-7.
[http://dx.doi.org/10.5530/ijopp.11.1.10]
[14]
Roujeau JC. The spectrum of Stevens-Johnson syndrome and toxic epidermal necrolysis: a clinical classification. J Invest Dermatol 1994; 102(6): 28S-30S.
[http://dx.doi.org/10.1111/1523-1747.ep12388434] [PMID: 8006430]
[15]
Sassolas B, Haddad C, Mockenhaupt M, et al. ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson Syndrome and toxic epidermal necrolysis: comparison with case-control analysis. Clin Pharmacol Ther 2010; 88(1): 60-8.
[http://dx.doi.org/10.1038/clpt.2009.252] [PMID: 20375998]
[16]
Kardaun SH, Sidoroff A, Valeyrie-Allanore L, et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol 2007; 156(3): 609-11.
[http://dx.doi.org/10.1111/j.1365-2133.2006.07704.x] [PMID: 17300272]
[17]
Voora L, Shastry C, Bhandari R, Sukeerthi D, Rawal KB, Chand S. Phenytoin-induced erythroderma. J Young Pharm 2019; 11(3): 320-1.
[http://dx.doi.org/10.5530/jyp.2019.11.65]
[18]
Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30(2): 239-45.
[http://dx.doi.org/10.1038/clpt.1981.154] [PMID: 7249508]
[19]
Nayak S, Acharjya B. Adverse cutaneous drug reaction. Indian J Dermatol 2008; 53(1): 2-8.
[http://dx.doi.org/10.4103/0019-5154.39732] [PMID: 19967009]
[20]
Thakkar S, Patel TK, Vahora R, Bhabhor P, Patel R. Cutaneous adverse drug reactions in a Tertiary Care Teaching Hospital in India: An intensive monitoring study. Indian J Dermatol 2017; 62(6): 618-25.
[http://dx.doi.org/10.4103/ijd.IJD_703_16] [PMID: 29263536]
[21]
Pudukadan D, Thappa DM. Adverse cutaneous drug reactions: clinical pattern and causative agents in a tertiary care center in South India. Indian J Dermatol Venereol Leprol 2004; 70(1): 20-4.
[PMID: 17642552]
[22]
Li LF, Ma C. Epidemiological study of severe cutaneous adverse drug reactions in a city district of China. Clin Exp Dermatol 2006; 31(5): 642-7.
[http://dx.doi.org/10.1111/j.1365-2230.2006.02185.x] [PMID: 16901302]
[23]
Ding WY, Lee CK, Choon SE. Cutaneous adverse drug reactions seen in a tertiary hospital in Johor, Malaysia. Int J Dermatol 2010; 49(7): 834-41.
[http://dx.doi.org/10.1111/j.1365-4632.2010.04481.x] [PMID: 20618508]
[24]
Ang CC, Wang YS, Yoosuff EL, Tay YK. Retrospective analysis of drug-induced hypersensitivity syndrome: a study of 27 patients. J Am Acad Dermatol 2010; 63(2): 219-27.
[http://dx.doi.org/10.1016/j.jaad.2009.08.050] [PMID: 20605253]
[25]
Kano Y, Ishida T, Hirahara K, Shiohara T. Visceral involvements and long-term sequelae in drug-induced hypersensitivity syndrome. Med Clin North Am 2010; 94(4): 743-59.
[http://dx.doi.org/10.1016/j.mcna.2010.03.004] [PMID: 20609861]
[26]
Mockenhaupt M. Severe drug-induced skin reactions: clinical pattern, diagnostics and therapy. J Dtsch Dermatol Ges 2009; 7(2): 142-60.
[http://dx.doi.org/10.1111/j.1610-0387.2008.06878.x] [PMID: 19371237]
[27]
Venkateswarlu K. phenytoin induced erythroderma reaction: A case report. J Pharm Res 2017; 6: 57-8.
[28]
Alvestad S, Lydersen S, Brodtkorb E. Rash from antiepileptic drugs: influence by gender, age, and learning disability. Epilepsia 2007; 48(7): 1360-5.
[http://dx.doi.org/10.1111/j.1528-1167.2007.01109.x] [PMID: 17484761]
[29]
Sullivan JR, Shear NH. Drug eruptions and other adverse drug effects in aged skin. Clin Geriatr Med 2002; 18(1): 21-42.
[http://dx.doi.org/10.1016/S0749-0690(03)00032-6] [PMID: 11913737]
[30]
Census of India: Age structure and marital status. 2013. Available from: http://www.censusindia.gov.in/Census-And-You/age-structure-and-marital-status.aspx
[31]
Sukasem C, Sririttha S, Tempark T, et al. Genetic and clinical risk factors associated with phenytoin-induced cutaneous adverse drug reactions in Thai population. Pharmacoepidemiol Drug Saf 2020; 29(5): 565-74.
[http://dx.doi.org/10.1002/pds.4979] [PMID: 32134161]
[32]
Census of India: India, Gender composition. 2013. Available from: http:// www.censusindia.gov.in/Census-And-Yoy/gender-composition
[33]
Balta I, Ozuguz P. Vitamin B12-induced acneiform eruption. Cutan Ocul Toxicol 2014; 33(2): 94-5.
[http://dx.doi.org/10.3109/15569527.2013.808657] [PMID: 23815241]
[34]
Al-Temini SAK. Factors influencing the occurrence of steroid acne. Iraqi J Community Med 2006; 3: 265-7.
[35]
Ravishankar M, Shweta S, Deepika G. Metasone furoate induced acneiform eruption. IJBCP 2017; 3(4): 2.
[36]
Jenkins RB, Ratner AC. Diphenylhydantoin and acne. N Engl J Med 1972; 287(3): 148.
[http://dx.doi.org/10.1056/NEJM197207202870314] [PMID: 4260678]
[37]
Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern Med 2003; 139(8): 683-93.
[http://dx.doi.org/10.7326/0003-4819-139-8-200310210-00012] [PMID: 14568857]
[38]
Alomar MJ. Factors affecting the development of adverse drug reactions (Review article). Saudi Pharm J 2014; 22(2): 83-94.
[http://dx.doi.org/10.1016/j.jsps.2013.02.003] [PMID: 24648818]
[39]
Joshi R, Tripathi M, Gupta P, Gulati S, Gupta YK. Adverse effects & drug load of antiepileptic drugs in patients with epilepsy: Monotherapy versus polytherapy. Indian J Med Res 2017; 145(3): 317-26.
[PMID: 28749393]
[40]
Anderson M, Egunsola O, Cherrill J, Millward C, Fakis A, Choonara I. A prospective study of adverse drug reactions to antiepileptic drugs in children. BMJ Open 2015; 5(6): e008298-8.
[http://dx.doi.org/10.1136/bmjopen-2015-008298] [PMID: 26033949]
[41]
Pichler WJ, Srinoulprasert Y, Yun J, Hausmann O. Multiple drug hypersensitivity. Int Arch Allergy Immunol 2017; 172(3): 129-38.
[http://dx.doi.org/10.1159/000458725] [PMID: 28315874]
[42]
Zaccara G, Franciotta D, Perucca E. Idiosyncratic adverse reactions to antiepileptic drugs. Epilepsia 2007; 48(7): 1223-44.
[http://dx.doi.org/10.1111/j.1528-1167.2007.01041.x] [PMID: 17386054]
[43]
Karimzadeh P, Bakrani V. Antiepileptic drug-related adverse reactions and factors influencing these reactions. Iran J Child Neurol 2013; 7(3): 25-9.
[PMID: 24665302]
[44]
Lim HY, Huang GK, Torresi J, Johnson D. Red herring in returned traveler: drug reaction with eosinophilia and systemic symptom (DRESS) syndrome mimicking sepsis. J Travel Med 2014; 21(6): 425-8.
[http://dx.doi.org/10.1111/jtm.12152] [PMID: 25345985]
[45]
Shiohara T, Mizukawa Y. Drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS): An update in 2019. Allergol Int 2019; 68(3): 301-8.
[http://dx.doi.org/10.1016/j.alit.2019.03.006] [PMID: 31000444]
[46]
George A, Girisha BS, Rao S. A perspective study of cutaneous manifestations in primary psychiatric disorders in a tertiary care hospital. Indian J Psychiatry 2018; 60(2): 213-6.
[http://dx.doi.org/10.4103/psychiatry.IndianJPsychiatry_156_18] [PMID: 30166678]
[47]
Messenheimer J, Mullens EL, Giorgi L, Young F. Safety review of adult clinical trial experience with lamotrigine. Drug Saf 1998; 18(4): 281-96.
[http://dx.doi.org/10.2165/00002018-199818040-00004] [PMID: 9565739]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy