ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. During clinical trials 45 (5%) of 905 patients treated with Ketoconazole Cream, 2% and (2.4%) of 208 patients treated with placebo reported side effects consisting mainly of severe irritation, pruritus and stinging. One of the patients treated with ketoconazole cream developed painful allergic reaction.In worldwide postmarketing experience, rare reports of contact dermatitis have been associated with ketoconazole cream or one of its excipients, namely sodium sulfite or propylene glycol. To report SUSPECTED ADVERSE REACTIONS, contact Encube Ethicals Private Limited at 1-833-285-4151 or FDA at 1-800- FDA-1088 or www.fda.gov/medwatch.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility. long-term feeding study in Swiss Albino mice and in Wistar rats showed no evidence of oncogenic activity. The dominant lethal mutation test in male and female mice revealed that single oral doses of ketoconazole as high as 80 mg/kg produced no mutation in any stage of germ cell development. The Ames Salmonella microsomal activator assay was also negative.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. When Ketoconazole Cream, 2% was applied dermally to intact or abraded skin of Beagle dogs for 28 consecutive days at dose of 80 mg, there were no detectable plasma levels using an assay method having lower detection limit of ng/ml.After single topical application to the chest, back and arms of normal volunteers, systemic absorption of ketoconazole was not detected at the ng/ml level in blood over 72-hour period.Two dermal irritancy studies, human sensitization test, phototoxicity study and photoallergy study conducted in 38 male and 62 female volunteers showed no contact sensitization of the delayed hypersensitivity type, no irritation, no phototoxicity and no photoallergenic potential due to Ketoconazole Cream, 2%. Microbiology: Ketoconazole is broad spectrum synthetic antifungal agent which inhibits the in vitro growth of the following common dermatophytes and yeasts by altering the permeability of the cell membrane: dermatophytes: Trichophyton rubrum, T. mentagrophytes, T. tonsurans, Microsporum canis, M. audouini, M. gypseum and Epidermophyton floccosum; yeasts: Candida albicans Malassezia ovale (Pityrosporum ovale) and C. tropicalis; and the organism responsible for tinea versicolor, Malassezia furfur (Pityrosporum orbiculare). Only those organisms listed in the INDICATIONS AND USAGE Section have been proven to be clinically affected. Development of resistance to ketoconazole has not been reported. Mode of Action: In vitro studies suggest that ketoconazole impairs the synthesis of ergosterol, which is vital component of fungal cell membranes. It is postulated that the therapeutic effect of ketoconazole in seborrheic dermatitis is due to the reduction of M. ovale, but: this has not been proven.

DESCRIPTION SECTION.

DESCRIPTION. Ketoconazole Cream, 2% contains the broad-spectrum synthetic antifungal agent, ketoconazole 2%. Each gram, for topical administration, contains ketoconazole 20 mg and is formulated in an aqueous cream vehicle consisting of propylene glycol, purified water, cetyl alcohol, stearyl alcohol, isopropyl myristate, sorbitan monostearate, polysorbate 60, polysorbate 80, and sodium sulfite, anhydrous: Ketoconazole is cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl] piperazine and has the following structural formula: M. Formula: 26H 28Cl 2N 4O M.W.: 531.44 Ketoconazole Structure.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Cutaneous candidiasis, tinea corporis, tinea cruris, tinea pedis, and tinea (pityriasis) versicolor: It is recommended that Ketoconazole Cream, 2% be applied once daily to cover the affected and immediate surrounding area. Clinical improvement may be seen fairly soon after treatment is begun; however, candidal infections and tinea cruris and corporis should be treated for two weeks in order to reduce the possibility of recurrence. Patients with tinea versicolor usually require two weeks of treatment Patients with tinea pedis require six weeks of treatment. If patient shows no clinical improvement after the treatment period, the diagnosis should be redetermined. Seborrheic dermatitis: Ketoconazole cream, 2% should be applied to the affected area twice daily for four weeks or until no clinical clearing. If patient shows no clinical improvement after the treatment period, the diagnosis should be redetermined.

GENERAL PRECAUTIONS SECTION.

General. If reaction suggesting sensitivity or chemical irritation should occur, use of the medication should be discontinued. Hepatitis (1:10,000 reported incidence) and, at high doses, lowered testosterone and ACTH induced corticosteroid serum levels have been seen with orally administered ketoconazole; these effects have not been seen with topical ketoconazole.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Ketoconazole Cream, 2% is supplied in 15, 30, and 60 gram tubes.15 tube (21922- 025-04)30 tube (21922- 025-05)60 tube (21922- 025-07)STORAGEStore at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Mfg Lic No. 361Manufactured by :Encube Ethicals Pvt. Ltd.Plot No. C-1, Madkaim Industrial Estate,Madkaim, Post: Mardol, Ponda,Goa 403 404, India. Distributed by: Encube Ethicals, Inc.200 Meredith Avenue, Suite 101ADurham, NC 27713 USA Rev: 03 May 2021 Encube logo.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Ketoconazole Cream, 2% is indicated for the topical treatment of tinea corporis, tinea cruris and tinea pedis caused by Trichophyton rubrum, T. mentagrophytes and Epidermophyton floccosum; in the treatment of tinea (pityriasis) versicolor caused by Malassezia furfur (Pityrosporum orbiculare); and in the treatment of cutaneous candidiasis caused by Candida spp. and in the treatment of seborrheic dermatitis.

NURSING MOTHERS SECTION.

Nursing Mothers. It is not known whether Ketoconazole Cream, 2% administered topically could result in sufficient systemic absorption to produce detectable quantities in breast milk. Nevertheless, decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL. Ketoconazole Cream 2%, 15 g; Carton Text KETOCONAZOLE CREAM 2% 21922-025-04 Rx only 15 FOR DERMATOLOGIC USE ONLY. Ketoconazole Cream 2%, 15 g; Tube Label KETOCONAZOLE CREAM 2% 21922-025-04 Rx only 15 FOR DERMATOLOGIC USE ONLY. Ketoconazole Cream 2%, 30 g; Carton Text KETOCONAZOLE CREAM 2% 21922-025-05 Rx only 30g FOR DERMATOLOGIC USE ONLY. Ketoconazole Cream 2%, 30 g; Tube Label KETOCONAZOLE CREAM 2% 21922-025-05 Rx only 30g FOR DERMATOLOGIC USE ONLY. Ketoconazole Cream 2%, 60 g; Carton Text KETOCONAZOLE CREAM 2% 21922-025-07 Rx only 60 FOR DERMATOLOGIC USE ONLY. Ketoconazole Cream 2%, 60 g; Tube Label KETOCONAZOLE CREAM 2% 21922-025-07 Rx only 60 FOR DERMATOLOGIC USE ONLY. Carton Text 15 gm. Tube label 15 gm. Carton Text 30 gm. Tube Label 30 gm. Tube Label 60 gm.

PRECAUTIONS SECTION.

PRECAUTIONS. General. If reaction suggesting sensitivity or chemical irritation should occur, use of the medication should be discontinued. Hepatitis (1:10,000 reported incidence) and, at high doses, lowered testosterone and ACTH induced corticosteroid serum levels have been seen with orally administered ketoconazole; these effects have not been seen with topical ketoconazole.. Carcinogenesis, Mutagenesis, Impairment of Fertility. long-term feeding study in Swiss Albino mice and in Wistar rats showed no evidence of oncogenic activity. The dominant lethal mutation test in male and female mice revealed that single oral doses of ketoconazole as high as 80 mg/kg produced no mutation in any stage of germ cell development. The Ames Salmonella microsomal activator assay was also negative. Pregnancy. Teratogenic effectsPregnancy Category CKetoconazole has been shown to be teratogenic (syndactylia and oligodactylia) in the rat when given orally in the diet at 80 mg/kg/day, (10 times the maximum recommended human oral dose). However, these effects may be related to maternal toxicity, which was seen at this and higher dose levels. There are no adequate and well-controlled studies in pregnant women. Ketoconazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.. Nursing Mothers. It is not known whether Ketoconazole Cream, 2% administered topically could result in sufficient systemic absorption to produce detectable quantities in breast milk. Nevertheless, decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.. Pediatric Use. Safety and effectiveness in children have not been established.

PREGNANCY SECTION.

Pregnancy. Teratogenic effectsPregnancy Category CKetoconazole has been shown to be teratogenic (syndactylia and oligodactylia) in the rat when given orally in the diet at 80 mg/kg/day, (10 times the maximum recommended human oral dose). However, these effects may be related to maternal toxicity, which was seen at this and higher dose levels. There are no adequate and well-controlled studies in pregnant women. Ketoconazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

WARNINGS SECTION.

WARNINGS. Ketoconazole Cream, 2% is not for ophthalmic use. Ketoconazole Cream, 2% contains sodium sulfite anhydrous, sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.