CLOTRIMAZOLE TOPICAL SOLUTION, USP 1%
0248
FOR DERMATOLOGIC USE ONLY
NOT FOR OPHTHALMIC USE

Clotrimazole, USP is a synthetic antifungal agent having the chemical name [1 (o-Chloro-α,α-diphenylbenzyl)imidazole]. It has the following structural formula:

C₂₂H₁₇ClN₂ M.W. 344.84

Clotrimazole is an odorless, white crystalline substance. It is practically insoluble in water, sparingly soluble in ether and very soluble in polyethylene glycol 400, ethanol and chloroform.

Each mL of clotrimazole topical solution contains 10 mg clotrimazole, USP in a nonaqueous vehicle of polyethylene glycol 400.

Clotrimazole is a broad spectrum antifungal agent that is used for the treatment of dermal infections caused by various species of pathogenic dermatophytes, yeasts, and Malassezia furfur. The primary action of clotrimazole is against dividing and growing organisms.

In vitro, clotrimazole exhibits fungistatic and fungicidal activity against isolates of Trichophytonrubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, Microsporum canis, and Candida species, including Candida albicans.

In general, the in vitro activity of clotrimazole corresponds to that of tolnaftate and griseofulvin against the mycelia of dermatophytes (Trichophyton, Microsporum, and Epidermophyton), and to that of the polyenes (amphotericin B and nystatin) against budding fungi (Candida). Using an in vivo (mouse) and an in vitro (mouse kidney homogenate) testing system, clotrimazole and miconazole were equally effective in preventing the growth of the pseudomycelia and mycelia of Candida albicans.

Strains of fungi having a natural resistance to clotrimazole are rare. Only a single isolate of Candida guilliermondi has been reported to have primary resistance to clotrimazole.

No single step or multiple step resistance to clotrimazole has developed during successive passages of Candida albicans and Trichophyton mentagrophytes. No appreciable change in sensitivity was detected after successive passages of isolates of C. albicans, C. krusei, or C. pseudotropicalis in liquid or solid media containing clotrimazole. Also, resistance could not be developed in chemically induced mutant strains of polyene resistant isolates of C. albicans. Slight, reversible resistance was noted in three isolates of C. albicans tested by one investigator. There is a single report that records the clinical emergence of a C. albicans strain with considerable resistance to flucytosine and miconazole, and with cross resistance to clotrimazole; the strain remained sensitive to nystatin and amphotericin B.

In studies of the mechanism of action, the minimum fungicidal concentration of clotrimazole caused leakage of intracellular phosphorus compounds into the ambient medium with concomitant breakdown of cellular nucleic acids and accelerated potassium efflux. Both these events began rapidly and extensively after addition of the drug.

Clotrimazole appears to be well absorbed in humans following oral administration and is eliminated mainly as inactive metabolites. Following topical and vaginal administration, however, clotrimazole appears to be minimally absorbed.

Six hours after the application of radioactive clotrimazole 1% cream and 1% solution onto intact and acutely inflamed skin, the concentration of clotrimazole varied from 100 mcg/cm³ in the stratum corneum to 0.5 to 1 mcg/cm³ in the stratum reticulare, and 0.1 mcg/cm³ in the subcutis. No measurable amount of radioactivity (< 0.001 mcg/mL) was found in the serum within 48 hours after application under occlusive dressing of 0.5 mL of the solution or 0.8 g of the cream. Only 0.5% or less of the applied radioactivity was excreted in the urine.

Following intravaginal administration of 100 mg ¹⁴C-clotrimazole vaginal tablets to nine adult females, an average peak serum level, corresponding to only 0.03 mcg equivalents/mL of clotrimazole, was reached one to two days after application. After intravaginal administration of 5 g of 1% ¹⁴C-clotrimazole vaginal cream, containing 50 mg active drug, to five subjects (one with candidal colpitis), serum levels corresponding to approximately 0.01 mcg equivalents/mL were reached between 8 and 24 hours after application.

Clotrimazole topical solution is indicated for the topical treatment of candidiasis due to Candida Albicans and tinea versicolor due to Malassezia furfur.

Clotrimazole is also available as a nonprescription li which is indicated for the topical treatment of the following dermal infections: tinea pedis, tinea cruris, and tinea corporis due to Trichophytonrubrum, Trichophytonmentagrophytes, Epidermophytonfloccosum, and Microsporumcanis.

Clotrimazole topical solution is contraindicated in individuals who have shown hypersensitivity to any of their components.

Clotrimazole topical solution is not for ophthalmic use.

If irritation or sensitivity develops with the use of clotrimazole, treatment should be discontinued and appropriate therapy instituted.

This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

The patient should be advised to:

• Use the medication for the full treatment time even though the symptoms may have improved. Notify the physician if there is no improvement after four weeks of treatment.
• Inform the physician if the area of application shows signs of increased irritation (redness, itching, burning, bulering, swelling, oozing) indicative of possible sensitization.
• Avoid the use of occlusive wrappings or dressings.
• Avoid sources of infection or reinfection.

If there is lack of response to clotrimazole, appropriate microbiological studies should be repeated to confirm the diagnosis and rule out other pathogens before instituting another course of antimycotic therapy.

Synergism or antagonism between clotrimazole and nystatin, or amphotericin B, or flucytosine against strains of C. albicans has not been reported.

An 18 month oral dosing study with clotrimazole in rats has not revealed any carcinogenic effect.

In tests for mutagenesis, chromosomes of the spermatophores of Chinese hamsters which have been exposed to clotrimazole were examined for structural changes during the metaphase. Prior to testing, the hamsters had received five oral clotrimazole doses of 100 mg/kg body weight. The results of this study showed that clotrimazole had no mutagenic effect.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when clotrimazole is used by a nursing woman.

Safety and effectiveness in pediatric patients have been established for clotrimazole when used as indicated and in the recommended dosage.

The following adverse reactions have been reported in connection with the use of clotrimazole: erythema, stinging, bulering, peeling, edema, pruritus, urticaria, burning, and general irritation of the skin.

Acute overdosage with topical application of clotrimazole is unlikely and would not be expected to lead to a life threatening situation.

Gently massage sufficient clotrimazole topical solution into the affected and surrounding skin areas twice a day, in the morning and evening.

Clinical improvement, with relief of pruritus, usually occurs within the first week of treatment with clotrimazole topical solution. If the patient shows no clinical improvement after four weeks of treatment with clotrimazole topical solution, the diagnosis should be reviewed.

Clotrimazole Topical Solution, USP 1% is supplied in 10 mL and 30 mL plastic squeeze bottles.

Store between controlled room temperature, between 20° and 25°C (68° and 77°F) (see USP).

Manufactured By:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. F 4/2003

I20913