Topical antifungal-corticosteroid fixed-drug combinations: Need for urgent action.

Sir,

Superficial dermatophytosis, commonly known as ringworm or tinea, is a common fungal infection affecting over 20% of the population worldwide. Recently, the prevalence of superficial dermatophytosis has seen an alarming rise and ranges from 36.6% to 78.4% in different regions of India, and the present situation has been described by some experts as the “Great Indian Epidemic of Superficial Dermatophytosis.”[1] Indiscriminate use of fixed-drug combination (FDC) of corticosteroids with one or more antifungal and antibacterial agents has been cited as a major reason for the emergence of chronic, atypical, recurrent, recalcitrant, and treatment-resistant cases of superficial dermatophytosis in epidemic proportion.

In India, FDC creams containing steroid, antifungal, and antibacterial cocktails are easily available over the counter. These steroid cocktails are often used by patients as self-medication, for symptomatic relief without supervision by a trained specialist. People stop their use as the itching and redness disappear and reuse as symptoms remerge.[1] Some of these steroid-antifungal cocktails cost lesser than the pure antifungal creams, provide quick symptomatic relief, and are easily available over the counter which makes them popular [Table 1]. These formulations account for over half of the sales of all topical steroids in the Indian market.

Table 1

Commonly available topical antifungal preparations and their fixed drug combinations in Indian markets

Topical antifungal	Preparation cost (INR/15 g)	Average cost (INR/15 g)	Topical FDCs of antifungal agenst with corticosteroids	Preparation cost (INR/15 g)	Average cost (INR/15 g)
Miconazole (cream/ointment 2% w/w)	A-24	38.50	Miconazole 2% + clobetasol proprionate 0.05% + neomycin 0.5% (A-G)	A-11.4	73.36
	B-27.25			B-42
	C-28			C-49
	D-35			D-60
	E-35			E-72
	F-37.5			F-80
	G-42			G-87
	H-80		Miconazole 2% + clobetasol proprionate 0.05% + gentamycin 0.1% (H-I)	H-49
				I-89
			Miconazole 2% + beclomethasone 0.025% + neomycin 0.5% (J-K)	J-47.7
				K-73
Clotrimazole (cream/ointment 1% w/w)	A-23	38.17	Clotrimazole 1% + beclomethasone 0.025% + neomycin 0.5% (A-G)	A-37.5	52.17
	B-27			B-39
	C-33.49			C-45
	D-38			D-48
	E-45.78			E-49
	F-50			F-55
	G-50			G-73.5
			Clotrimazole 1% + beclomethasone 0.025% + gentamycin 0.1% (H-J)	H-37.5
				I-57.55
				J-108.8
			Clotrimazole 1% + betamethasone 0.05% + gentamycin 0.1% (K)	K-23.9
Terbinafine (cream/ointment 1% w/w)	A-49	69.00	Terbinafine 2% + clobetasol proprionate 0.05% + ofloxacin 0.75% + ornidazole 2% (A-F)	A-57	67.00
	B-58			B-58
	C-60			C-60
	D-64			D-60
	E-75			E-72
	F-87			F-80
	G-90		Terbinafine 2% + clobetasol proprionate 0.05%+ ciprofloxacin 1% + metronidazole 1% (G-H)	G-72
				H-77
Ketoconazole (cream/ointment 2% w/w)	A-45	69.50	Ketoconazole 2% + clobetasol proprionate 0.05% +gentamycin 0.1% (A)	A-80	81.16
	B-49.5		Ketoconazole 2% + clobetasol proprionate 0.05% + gentamycin 0.1% + tolnaftate 1% (B)	B-80
	C-55		Ketoconazole 2% + clobetasol proprionate 0.05% + neomycin 0.5% (C)	C-96
	D-77.5		Ketoconazole 2% + clobetasol proprionate 0.05% + neomycin 0.5% + tolnaftate 1% (D)	D-77
	E-90		Ketoconazole 2% + fluocinolone acetonide 0.1% + neomycin 0.5% (E-F)	E-77
	F-100			F-77

FDCs=Fixed drug combinations

Evidence from well-controlled studies suggests that the use of steroid-antifungal combination is not superior to a single antifungal agent and has lower mycological and clinical cure rates in the management of dermatophytosis.[2] A double-blind comparison of naftifine cream and clotrimazole/betamethasone dipropionate cream in the treatment of tinea pedis by Smith et al. showed a mycological cure rate of 73% with naftifine and only 43% with the steroidal FDC, at 4 weeks of treatment. Smith et al. also reported a 3–4 times higher relapse rates and adverse drug reactions with clotrimazole/betamethasone dipropionate cream as compared to naftifine alone.[3] These FDCs are therefore not routinely recommended unless there is a heavy inflammatory component in an otherwise healthy adult with good compliance and severe symptoms, which is causing impairment in daily activities.[2] While there may be a scientific merit in using topical corticosteroids with antifungal agent for a fungal infection, adding antibiotics in a preparation meant for treating fungal infection cannot be justified.

The expert consensus from India has also strongly discouraged the use of topical corticosteroids in the management of dermatophytosis. To stop the irrational use of topical corticosteroids, the Indian Association of Dermatologist, Venereologist, and Leprologist (IADVL) took an initiative to form a special task force called IADVL Taskforce against Topical Steroid Abuse. The Taskforce had recommended the DCGI to bring topical steroids under schedule-H; to include schedule-H1 warning on package insert for potent topical corticosteroid; and to immediately enforce ban on all the irrational FDCs of topical corticosteroids with antifungal, antibacterial, and skin-lightening agents. The DCGI through a gazette notification under section 26A of the Drugs and Cosmetics Act, 1940, on March 10, 2016, enforced a ban on manufacture of 349 irrational FDCs.[4] However, the Honorable Delhi High Court granted a stay on the same to pharmaceutical industry and sought expert opinion from the Drugs Technical Advisory Board (DTAB).[4] The DTAB constituted a subcommittee which recommended the ban of 343 FDCs and regulatory restrictions on six FDCs. On September 14, 2018, based on the recommendation of DTAB and its subcommittee, the DCGI banned 328 FDCs on safety concerns, exempting 15 FDCs which were approved before 1988, as the new drug definition and its related provisions were introduced in the Drugs and Cosmetics Act after September 21, 1988. However, this ban was revoked on February 5, 2019, and the manufacturers are requested to submit precise data of efficacy and safety with respect to these FDCs.[5]

Topical corticosteroids are potent agents that are used in a variety of inflammatory skin disorders; however, at the same time, their easy availability and inappropriate use as FDCs are causes for concern in the country. Strict enforcement of existing drug regulations is urgently needed to stop marketing of irrational antifungal and steroid FDCs across the country. The State Licensing Authority (SLA) should immediately revoke the marketing license of such irrational FDCs and ensure that only those FDCs that are approved by the DCGI are permitted for manufacturing and marketing in their state. The pharmaceutical industry should withdraw such irrational FDCs from markets in the public interest. They should collaborate with scientific community and lay emphasis on the development of more effective and safe antifungal agents.

The topical antifungal therapy given to a patient needs to be specific and tailored depending on individual needs. It must be based on the standard treatment guidelines. The medical students, doctors, and pharmacists should be educated to prevent indiscriminate use of topical corticosteroids while treating superficial dermatophytosis. With the availability of broad-spectrum antifungal agents like naftifine which have inherent anti-inflammatory properties, prescribing of topical steroidal FDC can be further avoided. Some antifungal creams and their FDCs are advertised to consumers by pharmaceutical companies for treating superficial fungal infections which promote irrational use. Any such direct advertisement of topical antifungal creams and their FDCs should not be done, and the general public must also be made aware of the potential harms of their self-medication. A team approach by involving all the stakeholders such as drug regulators, pharmaceutical industry, physician, pharmacist, and patients is needed to ensure rational use of topical corticosteroids and their FDCs.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.