KETOCONAZOLE - ketoconazole cream 
Tiber Laboratories

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Ketoconazole
Cream, 2%

Rx only

DESCRIPTION

Ketoconazole cream, 2% contains the broad-spectrum synthetic antifungal agent, ketoconazole 2%, formulated in an aqueous cream vehicle consisting of butylated hydroxyanisole (BHA), cetyl alcohol, isopropyl myristate, polysorbate 60, polysorbate 80, propylene glycol, purified water, sorbitan monostearate and stearyl alcohol.

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:

Chemical Structure

Molecular Formula:  C26H28Cl2N4O4

Molecular Weight:  531.43

CLINICAL PHARMACOLOGY

When ketoconazole cream, 2% was applied dermally to intact or abraded skin of beagle dogs for 28 consecutive days at a dose of 80 mg, there were no detectable plasma levels using an assay method having a lower detection limit of 2 ng/mL.

After a single topical application to the chest, back and arms of normal volunteers, systemic absorption of ketoconazole was not detected at the 5 ng/mL level in blood over a 72-hour period.

Two dermal irritancy studies, a human sensitization test, a phototoxicity study and a 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 a 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 a 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.

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); in the treatment of cutaneous candidiasis caused by Candida spp. and in the treatment of seborrheic dermatitis.

CONTRAINDICATIONS

Ketoconazole cream, 2% is contraindicated in persons who have shown hypersensitivity to the active or excipient ingredients of this formulation.

WARNINGS

Ketoconazole cream, 2% is not for ophthalmic use.

PRECAUTIONS

General

If a 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

A 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 effects

Pregnancy Category C

Ketoconazole 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, a 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.

ADVERSE REACTIONS

During clinical trials 45 (5.0%) of 905 patients treated with ketoconazole cream, 2% and 5 (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 a painful allergic reaction.

In worldwide postmarketing experience, rare reports of contact dermatitis have been associated with ketoconazole cream or one of its excipients, namely propylene glycol.

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.

Seborrheic dermatitis

Ketoconazole cream, 2% should be applied to the affected area twice daily for four weeks or until clinical clearing.

If a patient shows no clinical improvement after the treatment period, the diagnosis should be redetermined.

HOW SUPPLIED

Ketoconazole cream, 2% is supplied in 60 g (NDC 23589-054-60) tubes.

Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].

Manufactured by:
Taro Pharmaceuticals Inc., Brampton, Ontario, Canada L6T 1C1

Manufactured for:
TIBER LABORATORIES, Suwanee, GA 30024

Issued: April, 2010
REV. 04/10 054-10

PK-6519-0
97

PRINCIPAL DISPLAY PANEL - 60 g Tube Carton

NDC 23589-054-60

Ketoconazole
Cream 2%

TIBER
LABORATORIES

FOR DERMATOLOGIC USE ONLY.
NOT FOR OPHTHALMIC USE.

60 g

Keep this and all medications out of the reach of children.

Rx only

PRINCIPAL DISPLAY PANEL - 60 g Tube Carton

KETOCONAZOLE 
ketoconazole   cream
Product Information
Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 23589-054
Route of Administration TOPICAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Ketoconazole (Ketoconazole) Ketoconazole 20 mg  in 1 g
Inactive Ingredients
Ingredient Name Strength
Butylated Hydroxyanisole  
cetyl alcohol  
isopropyl myristate  
polysorbate 60  
polysorbate 80  
propylene glycol  
water  
sorbitan monostearate  
stearyl alcohol  
Product Characteristics
Color WHITE Score     
Shape Size
Flavor Imprint Code
Contains     
Packaging
# NDC Package Description Multilevel Packaging
1 23589-054-60 1 TUBE In 1 CARTON contains a TUBE
1 60 g In 1 TUBE This package is contained within the CARTON (23589-054-60)

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA075638 12/18/2002

Labeler - Tiber Laboratories (008913939)
Establishment
Name Address ID/FEI Operations
Taro Pharmaceuticals Inc. 206263295 MANUFACTURE
Revised: 09/2010 Tiber Laboratories