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A comparative study to evaluate efficacy, safety and cost- effectiveness between Whitfield’s ointment + oral versus topical 1% butenafine in tinea infections of skin

Saket J. Thaker, Dimple S. Mehta, Hiral A. Shah1, Jayendra N. Dave1, Kunjan M. Kikani2

ABSTRACT

Aims and Objectives: The aim of this study is to compare the efficacy, safety and cost-effectiveness of topical Whitfield’s ointment plus oral fluconazole with topical 1% Departments of Pharmacology, butenafine in tinea infections of the skin. 1Dermatology Venereology and Materials and Methods: Patients were randomly allocated to the two treatment groups Leprology, and 2Microbiology, and advised to apply either agent topically twice-a-day for 4 weeks on the lesions and C.U. Shah Medical College, fluconazole (150 mg) was administered once a week for 4 weeks in the study group Surendranagar, Gujarat, India applying Whitfield’s ointment. Patients were followed-up at an interval of 10 days for clinical score and global evaluation response was assessed at baseline and during each Received: 29-08-2012 follow-up. Revised: 09-04-2013 Results: Out of 120 patients enrolled in the study 103 completed the study. Patients Accepted: 03-07-2013 treated with Whitfield’s ointment and oral fluconazole reduced mean sign and symptom Correspondence to: score from 8.81 ± 0.82 to 0.18 ± 0.59 while butenafine treated patients reduced it from Dr. Saket J. Thaker, 8.88 ± 0.53 to 0.31 ± 0.67 at the end of the treatment. Nearly, 98% patients were completely rd E-mail: [email protected] cleared of the lesion on the 3 follow-up with both treatments. Conclusion: Whitfield’s ointment with oral fluconazole is as efficacious, safe and cost- effective as compared with 1% butenafine in tinea infections of the skin.

KEY WORDS: Butenafine, fluconazole, tinea infections, Whitfield’s ointment

Introduction in tinea infections of the skin. The primary objective was to assess the cure rate, relapse, safety and cost-effectiveness of Dermatophytoses are fungal infections of keratinized tissue both treatments while secondary objective was to assess the (hair, skin, and nails).[1] Whitfield’s ointment is one of the oldest Clinicomycological correlation and to study the distribution of and cheapest agent containing 3% of different species of tinea. and 6% of benzoic acid.[2,3] Fluconazole is a fungistatic that impairs fungal cell wall synthesis by inhibiting the enzyme Materials and Methods 14-α lanosterol demethylase.[4] Their combination enhances The study was registered with Clinical Trial Registry of India the efficacy and minimizes the chances of relapse. Butenafine is a group of fungicidal drug, which impairs (CTRI/2012/08/002914 and was approved by ethics committee fungal cell wall synthesis by inhibiting the enzyme squalene of the teaching hospital. It was a prospective, randomized, epoxidase.[4] The present study was under taken to compare open-label, controlled, comparative clinical study, conducted in the efficacy, safety and cost-effectiveness of topical Whitfield’s patients attending the skin out-patient Department of C U Shah ointment plus oral fluconazole with topical 1% butenafine Medical College and Hospital, Surendranagar from May 2009 to November 2009. Diagnosis of tinea infections was performed

Access this article online by the Dermatologist. Patients newly diagnosed with tinea Quick Response Code: infections of skin were included in the study while follow-up Website: www.ijp-online.com cases, pregnant or lactating women, patients having an allergy DOI: 10.4103/0253-7613.121378 to or were excluded. All patients were explained about the study and written informed consent was obtained. Patients were randomly allocated in two groups. Group A received topical Whitfield’s ointment to be applied twice-a-day for 4 weeks plus oral fluconazole (150 mg once a

622 Indian Journal of Pharmacology | December 2013 | Vol 45 | Issue 6 week for 4 weeks) while Group B received topical 1% butenafine Graph Pad Instat 3.0 was used for the statistical analysis. cream twice-a-day for 4 weeks. All patients were administered Normality of the data was checked by Kolmogorov Smirnov oral chlorpheniramine maleate (4 mg) twice-a-day for a month test. Mann Whitney test was used to compare the groups to relieve pruritus. Whitfield’ ointment, fluconazole (150 mg) with respect to age. Fisher’s exact test was used to find the and 1% butenafine were purchased from the pharmacy store difference in both groups in terms of gender distribution. of the hospital. Baseline comparison of sign and symptom score between the Skin scraping was collected on the slides having 1-2 drops of groups was performed by Mann Whitney test. Total score of 20% KOH and observed under ×10 and ×45 of the microscope erythema, pruritus and scaling before and after treatment at each follow-up [Figure 1].[1,5] The scraping were cultured was compared by Wilcoxon matched pair test. Chi-square on the plates of Sabouraud’s agar supplemented with 1% test was used to compare global evaluation score between chloramphenicol in the incubator at 32-35°C for 7-10 days. The both groups at each follow-up. P < 0.05 was considered to species were identified by lactophenol cotton blue preparation. be statistically significant. Cost-effectiveness was calculated Photographs of both gross cultures and microscopic appearance on the basis of total expenditure incurred on medicines, cost of lactophenol cotton blue preparation were taken. Patients were of conveyance at the end of treatment in ` Indian rupee and followed-up at the interval of 10 days for 4 weeks to assess the cure rate in percentage. Incremental cost (ΔC) and incremental [9] relapse. Outcome of the treatment was assessed by the clinical effectiveness (ΔE) were calculated. [6,7] and mycological care. Results Clinical cure was assessed by scoring of three parameters Out of 120 patients enrolled in the study, 8 patients from that is erythema; pruritus and scaling, Each parameter was group A and 9 patients from group B were lost to follow-up and categorized into - mild - 1, moderate - 2, severe - 3. Global 103 patients completed the study. Evaluation Response was assessed at each follow-up.[7] Mycological cure was assessed by examining skin scraping Demographic Characteristics microscopically and culture. Both KOH and culture negative Median age in both groups was 35 years. Both groups were specimens were considered mycologically cured. also similar in terms of gender distribution (P = 0.1209). Tinea corporis was the most common diagnosis (37.84%) followed Statistical Analysis by tinea corporis and cruris mixed infection (30%). Most of the Sample size calculation patients (96.12%) were suffering from severe tinea infections Sample size was calculated by nMaster 1.0. As no previous at the first visit. Trichophyton mentagrophytes (60.94%) was studies have been conducted between combination of Whitfield’s the most common species followed by ointment and oral fluconazole, a pilot study on 10 patients was (28.12%). carried out to assess the cure rate. As per the result of the pilot Efficacy study, cure rate with Whitfield’s ointment + oral fluconazole was Combination of Whitfield’s ointment and oral fluconazole [8] taken as 90% and as per study by Tschen et al. cure rate with treatment and butenafine significantly reduced mean sign and butenafine was taken as 88%. Assuming population difference symptom score (P < 0.0001). Global Evaluation Response revealed of proportions as 0.085, setting alpha error at 5% and power that skin lesions were completely cleared with Whitfield’s ointment of study at 80% and using two sided test, 104 patients were + oral fluconazole and butenafine creamin majority of the patients needed. Assuming a dropout rate of approximately 15 20%, a (98%) [Table 1]. At the end of treatment, 97% of the patients in both total 120 patients were enrolled for the study. groups were mycologically cured and no relapse was observed in both treatment groups at the end of 4 weeks.

Figure 1: Butenafine is less cost-effective as compared to the Safety combination treatment of Whitfield’s ointment and oral fluconazole. Both drug treatments were well-tolerated. However, two ∆C-Incremental cost, ∆E-Incremental effectiveness, L-line – Line patients complained of burning and one patient complained of passing from 0–, Red Dot-Showing cost-effectiveness redness with Whitfield’s ointment. Gastritis was reported in one patient with fluconazole. No adverse event was reported with 1% butenafine. Cost-Effectiveness Cost per patient for complete treatment for Whitfield’s ointment plus fluconazole was ` 293.49, while that for butenafine was ` 707.60. ΔC was ` 414.11 and ΔE was 0.08 (ΔE). The line passing from 0 is called L-line. The zone below the line is acceptable zone. In the present study, the difference lies above L-line shown by the red dot. This represents that butenafine was less cost-effective as compared to Whitfield’s ointment + oral fluconazole. Discussion This study combined Whitfield’s ointment and oral fluconazole to minimize the chances of relapse as both are

Indian Journal of Pharmacology | December 2013 | Vol 45 | Issue 6 623 Table 1:

Global evaluation response of patient treated with Wf+flu and topical butenafine at different time interval

Response Follow-up 1 Follow-up 2 Follow-up 3 Wf+flun (%) Butenafinen (%) Wf+flu (%) Butenafine (%) Wf+flun (%) Butenafine (%) Cleared 00 (0) 00 (0) 40 (76.92) 32 (62.74) 51 (98.08) 50 (98) Excellent 49 (94.23) 41(80.39) 11 (21.15) 18 (35.29) 01 (1.92) 01 (2) Good 02 (3.85) 08 (15.69) 01 (1.92) 01 (1.96) 0 (0) 0 (0) Fair 01 (1.92) 02 (3.92) 0 (0) 0 (0) 0 (0) 0 (0) Values are in absolute numbers. Wf+flu=Whitfield’s ointment plus fluconazole

fungistatic and most of the patients in the study were suffering Acknowledgment from severe tinea infections justifying their combination We are thankful to the Dean of the institute for allowing us to carry while butenafine being fungicidal reduces the chance of out the study in the hospital and are also grateful to all participated relapse when used singly.[10] The present study showed that in the study. 80.77% of the patients were completely cleared of the lesion References clinically and mycologically at the end of second follow-up (20 days) and 98.08% were completely cleared at third 1. Sobera JO, Elewski BE. Fungal diseases. In: Bolognia JL, Jorizzo JL, Rapini RP, editors. Dermatology. 2nd ed. USA: Mosby Elsevier; 2008. p. 1135-63. follow-up (30 days) with topical Whitfield’s ointment plus 2. Brunton LS, Lazo JS, Parker KL. Antifungal drugs. In: Brunton LS, Lazo JS, oral fluconazole. In a study by Crevits et al., 82% (37/45) of Parker KL, editors. Goodman and Gilman’s The Pharmacological Basis of patients by oral fluconazole had shown complete clearance Therapeutics. 11th ed. USA: McGraw-Hill Publication; 2008. p. 1225-42. of the lesion, 90% and 88% respectively for tinea corporis 3. Gooskens V, Pönnighaus JM, Clayton Y, Mkandawire P, Sterne JA. Treatment [11] of superficial mycoses in the tropics: Whitfield’s ointment versus . and cruris respectively. Whitfield’s ointment produced Int J Dermatol 1994;33:738-42. 67% clinical cure at the end of 3 weeks treatment.[12] 4. Tripahi KD. Antifungal drugs. In: Tripathi KD, editor. Essentials of Medical This study demonstrated that 62.74% of the patients Pharmacology. 6th ed. New Delhi: Jaypee Brothers; 2008. p. 757-66. were completely cleared with the lesion clinically and 5. Verma S, Heffernan MP. Superficial fungal infection: , onychomycosis, tinea nigra, piedra. In: Wolff K, Goldsmith LA, Katz SI, Gilchrest mycollogically at the end of second follow-up (20 days) and BA, Paller AS, Leffell DJ, editors. Dermatology in General Medicine. 6th ed., Vol. 2. 98% were completely cleared at third follow-up (30 days) USA: McGraw Hill Inc.; 2003. p. 1989-2001. with topical 1% butenafine cream. Present study found 97% 6. McNeely W, Spencer CM. Butenafine. Drugs 1998;55:405-12. of the patients mycologically cured at the end of treatment 7. Jerajani HR, Amladi ST, Bongale R, Adepu V, Tendolkar UM, Sentamilselvi G, et al. Evaluation of clinical efficacy and safety of once daily topical administration of 1% in both groups. In the study by Tschen et al. in interdigital cream and lotion in dermatophytosis: An open label, non-comparative tinea pedis, 88% mycological cure was achieved at the end multicentre study. Indian J Dermatol Venereol Leprol 2000;66:188-92. of for weeks with the treatment of butenafine.[8] The present 8. Tschen E, Elewski B, Gorsulowsky DC, Pariser DM. Treatment of interdigital tinea study found no statistical significant difference between the pedis with a 4-week once-daily regimen of butenafine hydrochloride 1% cream. J Am Acad Dermatol 1997;36:S9-14. two groups in clearing of the lesion and in the development 9. Heitjan DF, Moskowitz AJ, Whang W. Bayesian estimation of cost-effectiveness of excellent clinical response (P > 0.05). In the butenafine ratios from clinical trials. Health Econ 1999;8:191-201. group, the score declined from a mean of 7.36 at baseline 10. Lesher JL Jr, Babel DE, Stewart DM, Jones TM, Kaminester L, Goldman M, to 1.5 ± f 2.3 at 8 weeks.[13] Burning, pruritus, striae and et al. Butenafine 1% cream in the treatment of : A multicenter, vehicle- controlled, double-blind trial. J Am Acad Dermatol 1997;36:S20-4. erythema with atrophy has been reported with topical 11. Crevits B, Picoto A, Staberg B, Urbanowski S, Silny W. Comparison of efficacy buetinafine[13] while no adverse drug reactions have been and safety of oral fluconazole and topical clotrimazole in the treatment of tinea observed with fluconazole.[14] Our results were synonymous corporis, tinea cruris, tinea pedis and cutaneous candidiasis. Curr Ther Res Clin with other existing studies, Moreover, no relapse was Exp 1998;59:503-10. 12. Wright S, Robertson VJ. An institutional survey of tinea capitis in Harare, observed in either groups during the 4 week surveillance Zimbabwe and a trial of cream versus Whitfield’s ointment in its period. Residual protection for 4 weeks with butenafine has treatment. Clin Exp Dermatol 1986;11:371-7. been reported.[8] Clayton and Connor et al. have reported that 13. Ramam M, Prasad HR, Manchanda Y, Khaitan BK, Banerjee U, Mukhopadhyaya A, et al. Randomised controlled trial of topical butenafine in tinea cruris and tinea transient burning and irritation with Whitfield ointment with corporis. Indian J Dermatol Venereol Leprol 2003;69:154-8. [15] relapse at the end of 4 weeks. Treatment with Whitfield’s 14. Assaf RR, Elewski BE. Intermittent fluconazole dosing in patients with ointment plus oral fluconazole was `414.11 cheaper than that onychomycosis: Results of a pilot study. J Am Acad Dermatol 1996;35:216-9. with 1% butenafine. Thus, it can be inferred that Whitfield’s 15. Clayton YM, Connor BL. Comparison of clotrimazole cream, Whitfield’s ointment and ointment for the topical treatment of ringworm infections, pityriasis ointment plus oral fluconazole is as efficacious as topical 1% versicolor, erythrasma and candidiasis. Br J Dermatol 1973;89:297-303. butenafine in tinea infections of the skin. Both treatments are safe and provide residual protection for 4 weeks after the Cite this article as: Thaker SJ, Mehta DS, Shah HA, Dave JN, Kikani KM. A comparative study to evaluate efficacy, safety and cost-effectiveness between completion of therapy. However, Whitfield’s ointment plus oral Whitfield's ointment + oral fluconazole versus topical 1% butenafine in tinea fluconazole is more cost-effective as compared with topical infections of skin. Indian J Pharmacol 2013;45:622-4. 1% butenafine in tinea infections of the skin. Source of Support: Nil, Conflict of Interest: No.

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