ATC Class:G01AF17

VA Class:DE102

AHFS Class:

• Azoles 84:04.08.08

Generic Name(s):

• Oxiconazole Nitrate

Chemical Name:

• 1-(2,4-Dichlorophenyl)-2-(1 H -imidazol-1-yl)ethanone ( Z )- O -[(2,4-Dichlorophenyl)methyl]oxime mononitrate

Molecular Formula:

• C₁₈H₁₃C₁₄N₃O•HNO₃

Oxiconazole nitrate, an imidazole derivative, is a synthetic azole antifungal agent.1,2,3,7,8,9,11,12,14,20,27,34,43

Dermatophytoses

Oxiconazole topical cream or lotion is used for the treatment of certain dermatophytoses, including tinea corporis (body ringworm),1,20,24,25,28 tinea cruris (jock itch),1,20,24,25 tinea pedis (athlete's foot),1,20,24,25 and tinea manuum† (hand ringworm),24,25 caused by Epidermophyton floccosum ,20,25,27,28 Microsporum canis †,20,25,27,28 M. gypseum †,25 Trichophyton mentagrophytes ,1,20,25,27,28 T. rubrum ,1,20,25,27,28 or T. verrucosum †.20,28

Results of controlled studies indicate that topical oxiconazole 1% cream is similar in efficacy and safety to topical miconazole nitrate 2% cream25 or topical econazole nitrate 1% cream27 for the treatment of dermatophytoses caused by susceptible organisms. In clinical studies, 2-4 weeks of therapy with topical oxiconazole 1% cream resulted in a clinical and mycologic cure in 86-93% of patients with tinea pedis, tinea corporis, or tinea cruris.20,24,27,28 Once-daily application of oxiconazole 1% cream appears to be as effective as twice-daily application of the cream for the topical treatment of these infections.1,20,24

Like other imidazole derivatives (e.g., clotrimazole, econazole, ketoconazole, miconazole, sulconazole) and ciclopirox olamine, oxiconazole has an advantage over some other topical antifungal agents (e.g., nystatin, tolnaftate) in the treatment of mixed infections or for empiric treatment pending identification of the causative organism, since the drug is active against both dermatophytes and Candida .32,33

Tinea Corporis and Tinea Cruris

Tinea corporis and tinea cruris generally can be effectively treated using a topical antifungal; however, an oral antifungal may be necessary if the disease is extensive, dermatophyte folliculitis is present, the infection is chronic or does not respond to topical therapy, or the patient is immunocompromised because of coexisting disease or concomitant therapy.35,36,39,40,41

Many clinicians consider topical imidazole-derivative azole antifungals (e.g., clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sulconazole) or topical allylamine antifungals (e.g., naftifine, terbinafine) the drugs of first choice for the topical treatment of tinea corporis or tinea cruris,36,43 although other topical antifungals (e.g., ciclopirox olamine, butenafine hydrochloride, tolnafate, undecylenic acid) also can be effective in the treatment of these infections.35,36,39,40,41

Tinea Pedis and Tinea Manuum

While topical antifungals usually are effective for the treatment of uncomplicated tinea pedis or tinea manuum,36,39,41 an oral antifungal usually is necessary for the treatment of hyperkeratotic areas on the palms and soles, for chronic moccasin-type (dry-type) tinea pedis, and for the treatment of tinea unguium (fingernail or toenail dermatophyte infections, onychomycosis).36,41

In a placebo-controlled study evaluating once- or twice-daily application of oxiconazole 1% lotion in patients with clinically and microbiologically established tinea pedis (64% with hyperkeratotic plantar tinea pedis; 28% with interdigital tinea pedis) caused by T. rubrum (77%), T. mentagrophytes (18%), or E. floccosum (4%), the mycologic cure rate 2 weeks after completion of therapy was 64% in those who received the drug once daily, 67% in those who received the drug twice daily, and 28% in those who received placebo.1 In studies evaluating oxiconazole 1% cream in patients with clinically and microbiologically established tinea pedis, the mycologic cure rate 2 weeks after completion of therapy was 79% in those who received the drug once daily, 77% in those who received the drug twice daily, and 33% in those who received placebo.1

Pityriasis (Tinea) Versicolor

Oxiconazole 1% topical cream is used for the treatment of pityriasis (tinea) versicolor, a superficial infection caused by Malassezia furfur ( Pityrosporum orbiculare or P. ovale ).1

Pityriasis (tinea) versicolor generally can be treated topically with an imidazole-derivative azole antifungal (e.g., clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sulconazole), an allylamine antifungal (e.g., terbinafine), ciclopirox olamine, or certain other topical therapies (e.g., selenium sulfide 2.5%).35,37,38,40,42 However, an oral antifungal (e.g., itraconazole, ketoconazole) may be indicated, with or without a topical antifungal, in patients who have extensive or severe infections or who fail to respond to or have frequent relapses with topical therapy.37,38,40

In 2 controlled trials evaluating the efficacy of oxiconazole 1% cream for the treatment of pityriasis (tinea) versicolor, patients received the drug or vehicle placebo once daily for 2 weeks.1 At 2 weeks after completion of treatment, the combined mycologic cure rate was 88% in those who received topical oxiconazole and 67% in those who received vehicle placebo.1

Cutaneous Candidiasis

Oxiconazole 1% cream is used for the topical treatment of cutaneous candidiasis† caused by Candida albicans or C. tropicalis .27,28

Other Uses

Although not commercially available in the US, oxiconazole has been used effectively as a 600-mg vaginal suppository for the treatment of vulvovaginal candidiasis†.23,26 Results of limited controlled studies indicate that the cure rate with intravaginal oxiconazole for vulvovaginal candidiasis is similar to that with intravaginal clotrimazole26 or econazole nitrate.23

Administration

Oxiconazole nitrate is applied topically to the skin as a 1% cream or a lotion.1

The cream or lotion should not be applied to the eye1 and should not be administered intravaginally.32,33

Oxiconazole lotion should be shaken well before using.1

A sufficient amount of oxiconazole 1% topical cream or lotion should be applied to the affected areas of skin and rubbed in gently.1

Dosage

Dosage and potency of oxiconazole nitrate are expressed in terms of oxiconazole.1

Dermatophytoses

For the topical treatment of tinea corporis, tinea cruris, or tinea pedis, oxiconazole 1% topical cream or lotion should be applied once or twice daily.1

The usual duration of therapy to reduce the possibility of recurrence is 2 weeks for tinea corporis and tinea cruris or 1 month for tinea pedis.1

If clinical improvement does not occur after the recommended treatment period, the diagnosis should be reevaluated.1

Pityriasis (Tinea) Versicolor

For the topical treatment of pityriasis (tinea) versicolor, oxiconazole 1% topical cream should be applied once daily.1

Pityriasis (tinea) versicolor should be treated for 2 weeks to reduce the possibility of recurrence.1 If clinical improvement does not occur after the recommended treatment period, the diagnosis should be reevaluated.1

Pityriasis (tinea) versicolor may give rise to hyperpigmented or hypopigmented patches on the trunk that may extend to the neck, arms, and upper thighs.1 Treatment of the infection may not immediately result in restoration of pigment to the affected sites.1 Normalization of pigment following successful therapy is variable and may take months, depending on individual skin type and incidental sun exposure.1 Although pityriasis (tinea) versicolor is not contagious, it may recur because the organism that causes the disease is part of the normal skin flora.1

Adverse Effects

Topically applied oxiconazole nitrate appears to have a low order of toxicity and generally is well tolerated.20,25,27,28 In clinical studies evaluating oxiconazole 1% cream, adverse effects occurred in about 4% of patients.1,28 Pruritus1,20 and burning1,20 were reported in 1-2%1 and irritation,1 stinging,1 erythema,1,20 rash,1 folliculitis,1 papules,1 nodules,1 maceration,1 and fissuring1 were reported in less than 1% of patients.1 Only rarely have irritation, pruritus, and burning been severe enough to require discontinuance of the drug.20 In a clinical study evaluating oxiconazole 1% lotion, adverse effects occurred in 2.6% of patients and included burning, stinging, pruritus, scaling, tingling, pain, and dyshidrotic eczema.1

Contact dermatitis has been reported rarely in patients receiving topical oxiconazole nitrate.1,21,22,47 Contact dermatitis also has been reported following topical application of other imidazole-derivative azole antifungals (e.g., clotrimazole, econazole miconazole, sulconazole, tioconazole).44,45,46,47,48 Cross-sensitization appears to occur among the imidazole derivatives;21,22,44,45,46,47,48 however, cross-sensitivity appears to be unpredictable.44,46,47,48

Adverse systemic effects have not been reported to date with topical oxiconazole nitrate.32,33

Precautions and Contraindications

Topical oxiconazole 1% cream and lotion are contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.1

Patients receiving topical oxiconazole nitrate should be instructed to use the medication for the full, prescribed treatment period, even if symptoms improve, and to contact their physician if their skin condition does not improve after a full course of therapy.1

Patients should be instructed to contact their physician if signs or symptoms of increased irritation, pruritus, burning, blistering, swelling, or oozing occur.1,32,33

If a reaction suggesting sensitivity, chemical irritation, or epidermal irritation occurs during treatment with oxiconazole nitrate, the drug should be discontinued and appropriate therapy initiated.1

The fact that patients with contact sensitivity to one imidazole-derivative azole antifungal may be sensitive to other similar drugs should be considered.45,46,47,48

Commercially available oxiconazole nitrate cream or lotion is intended for topical application to the skin only and should not be applied to the eye1 and should not be administered intravaginally.1,32,33

Pediatric Precautions

Topical oxiconazole 1% cream may be used for the treatment of tinea corporis, tinea cruris, tinea pedis, or pityriasis (tinea) versicolor in pediatric patients; however, such uses for which the drug has been shown to be effective rarely occur in those younger than 12 years of age.1 In a study evaluating use of oxiconazole 1% cream in children 10 years of age or younger, skin erythema occurred in one child and another was reported to have eczema-like skin alterations.1

The safety and efficacy of oxiconazole 1% lotion have not been established in children.1

Geriatric Precautions

Only a limited number of patients 65 years of age or older have been treated with oxiconazole 1% cream or lotion in clinical trials.1 Because available data to date indicate that adverse effects reported in geriatric patients are similar to those reported in younger adults, dosage adjustment is not recommended in geriatric patients.1

Mutagenicity and Carcinogenicity

Oxiconazole nitrate was not mutagenic when tested in vitro for induction of microbial point mutations in the Salmonella mutagen (Ames) test or the Chinese hamster V79 test.1 There also was no evidence of mutagenicity when oxiconazole nitrate was tested in vitro for chromosome breaks in the peripheral blood lymphocyte test or in vivo in the micronucleus assay in mice.1 Long-term animal studies to determine the carcinogenic potential of the drug have not been performed to date.1

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rabbits, rats, and mice using oxiconazole dosages of up to 100, 150, and 200 mg/kg daily, respectively, have not revealed evidence of harm to the fetus.1 There are no adequate and controlled studies to date using topical oxiconazole nitrate in pregnant women, and the drug should be used during pregnancy only when clearly needed.1

Fertility

Reproduction studies in female rats using oral oxiconazole dosages up to 3 mg/kg daily or in male rats using oral dosages up to 15 mg/kg daily have not revealed evidence of impaired fertility.1 However, when higher dosages were used, a reduction in fertility parameters in both males and females occurred, including a reduction in the number of sperm in vaginal smears, extended estrus cycles, and a decrease in mating frequency.1

Lactation

Since oxiconazole is distributed into milk,1,32 the manufacturer recommends that the drug be used topically with caution in nursing women.1

Since only low amounts of oxiconazole nitrate are absorbed following topical application to skin,1,10,20 drug interactions are unlikely in patients receiving usual topical dosage of the drug. No formal drug interaction studies have been performed to date.1

Acute Toxicity

Limited information is available on the acute toxicity of oxiconazole nitrate. The oral, IV, and intraperitoneal LD₅₀s of the drug are 3700-4000, 34-62, and 359-589 mg/kg daily, respectively, in mice.32 When oxiconazole 5% cream (5 times the concentration of the currently marketed preparation) was applied at a rate of 1 g/kg to approximately 10% of the body surface area of male and female rats for 35 days, 3 deaths and severe dermal inflammation were reported.1 Overdosage in humans following use of oxiconazole 1% cream or lotion has not been reported to date.1

Mechanism of Action

Oxiconazole usually is fungistatic in action3,7,8,34 but may be fungicidal in high concentrations or against very susceptible organisms.3,7,34

Like some imidazole derivatives (e.g., butoconazole, clotrimazole, econazole, ketoconazole, miconazole), oxiconazole presumably exerts its antifungal activity by altering cellular membranes, resulting in increased membrane permeability, secondary metabolic effects, and growth inhibition.3,4,5,9 Although the exact mechanism of action of oxiconazole has not been fully determined, it appears that the antifungal activity of the drug results from interference with ergosterol synthesis,1,4,5,9,34 probably via inhibition of C-14 methylation of sterol intermediates (e.g., lanosterol).4,5,9,34 Like some other imidazoles (e.g., clotrimazole, econazole, miconazole), oxiconazole suppresses ATP concentrations in intact cells and spheroplasts of Candida albicans .4 The mechanism of this ATP suppression is unknown and it is unclear whether this effect is related to the in vivo antifungal effects of the drug.4

Oxiconazole, like other imidazoles, has some antibacterial activity against aerobic gram-positive bacteria.3,20 However, this effect cannot be explained on the basis of inhibition of ergosterol synthesis since bacteria generally do not contain membrane sterols.29,30,31

Spectrum

Oxiconazole is active in vitro against many fungi, including dermatophytes and yeasts.1,2,3,7,11,12,14,20,34 The drug also has in vitro activity against some gram-positive bacteria.3,20

Like other imidazole derivatives, results of in vitro oxiconazole susceptibility tests are method dependent, and MIC values vary depending on the culture medium used, incubation temperature, pH, and inoculum size.2,3,7,11 In addition, currently available in vitro tests may not accurately reflect the in vivo susceptibility of some fungi (especially Candida ).2,3

Oxiconazole is active in vitro against Trichophyton mentagrophytes ,1,2,3,6,7,16 T. rubrum ,1,2,3,7 T. tonsurans ,1,7 T. violaceum ,1 Epidermophyton floccosum ,1,3,7 Microsporum audouinii ,1,7 M. canis ,1,2,3,7 and M. gypseum .1,3,7 Most susceptible strains of dermatophytes are inhibited in vitro by oxiconazole concentrations of 0.06-3 mcg/mL.3,7,11 In vitro on a weight basis, oxiconazole's activity against dermatophytes appears to be similar to that of econazole, ketoconazole, or miconazole.7,11 Oxiconazole also has some in vitro activity against Malassezia furfur ( Pityrosporum orbiculare )1,7 and Exophiala werneckii ,7 and the MIC₉₀ of the drug reported for these organisms is 16 and 0.25 mcg/mL, respectively.7

In vitro, oxiconazole is active against Candida albicans ,1,2,3,11,12,16 C. guilliermondii ,3 C. krusei ,2,3 C. parapsilosis ,2,3,11 C. tropicalis ,2,3,11 and Torulopsis glabrata .2,3,11 In vitro on a weight basis, oxiconazole's activity against C. albicans appears to be similar to that of ketoconazole and slightly less than that of miconazole.11 A wide range of oxiconazole MIC values have been reported for yeasts.3,11 The MIC₉₀ of oxiconazole ranges from 0.4-128 mcg/mL for C. albicans 3,11,12 and 4-100 mcg/mL for C. parapsilosis and C. tropicalis .3,11 In one in vitro study, the MIC₉₀ of the drug for T. glabrata was 0.5 mcg/mL.11

Oxiconazole concentrations of 0.025-0.3 mcg/mL generally inhibit Cryptococcus neoformans in vitro.3,11 The drug also is active in vitro against Aspergillus flavus ,2,3,11 A. fumigatus ,2,3,11 A. nidulans ,3 A. niger ,3 Petriellidium boydii ,11 and Sporothrix schenkii ,11 and these organisms generally are inhibited in vitro by concentrations of 1-32 mcg/mL.3,11

Oxiconazole is active in vitro against some aerobic gram-positive bacteria including Corynebacterium minutissimum ,20 Nocardia asteroides ,3 N. brasiliensis ,3 Streptomyces somaliensis ,3 and Actinomadura madurae .3

Resistance

Cross-resistance can occur among the azole antifungals.7,32 Several isolates of Candida albicans that were resistant to ketoconazole showed cross-resistance to oxiconazole and other imidazole-derivative antifungal agents as well as to triazole derivatives.32 Some strains of Malassezia furfur ( Pityrosporum orbiculare ) resistant to oxiconazole in vitro have been reported to be cross-resistant to econazole.7

Pharmacokinetics

Absorption

Following topical application to skin, only low concentrations are achieved systemically.1 In in vitro models using animal skin, oxiconazole was retained in the horny layer of the epidermis for up to 96 hours following topical application of a single dose of oxiconazole nitrate cream (1% oxiconazole).10,20 Following topical application of 2.5 mg/cm² of oxiconazole as a cream to human skin, concentrations of the drug in the epidermis, upper corneum, and deeper corneum were 7.97, 1.79, and 0.63 mg, respectively (16.2, 3.64, and 1.29 µmol, respectively), 5 hours later.1

Small amounts of oxiconazole are absorbed systemically when the drug is administered intravaginally.15 Following intravaginal administration of a single 150-mg dose of oxiconazole in healthy women, low concentrations of unchanged drug (32 ng/mL) are detectable in plasma 24 hours after the dose.15

Distribution

Following topical application of oxiconazole nitrate cream (1% oxiconazole) to human skin, the drug is distributed into the horny layer of the epidermis, corium, and subcutis.18,19 Oxiconazole also appears to penetrate into the nail plate following topical application.17,19

It is not known whether systemically absorbed oxiconazole crosses the placenta in humans or animals.32,33 Following subcutaneous administration of 5 mg/kg of oxiconazole in female rats, the ratio of milk/plasma concentrations of the drug 1.5-12 hours after the dose ranges from 3-8.1,32 The drug also is distributed into human milk.1,32

Elimination

Following topical application of oxiconazole nitrate cream (1% oxiconazole) to the skin of healthy individuals, less than 0.3% of the dose is excreted in urine within 5 days.1 It is unclear whether the concentration of oxiconazole excreted in urine following topical application corresponds to the amount of drug absorbed percutaneously,1 and it is not known whether the drug is excreted in feces following topical application.1

Chemistry and Stability

Chemistry

Oxiconazole nitrate, an imidazole derivative, is a synthetic azole antifungal agent.1,2,3,7,8,9,11,12,14,20,27,34 The drug occurs as a nearly white crystalline powder and is very slightly soluble in water and sparingly soluble in alcohol,1 having solubilities of approximately 0.4 and 12 mg/mL, respectively, at room temperature.32 The drug has a pK_a of approximately 6.2.32 For topical use, oxiconazole nitrate is commercially available as a white to off-white, opaque cream and lotion; both preparations are in a petrolatum base that contains benzoic acid as a preservative.1 The cream has a pH of 2.8-4.3.32 The drug also is available as a lotion.

Stability

Oxiconazole nitrate cream and lotion should be stored at 15-30°C.1 When stored as recommended, the commercially available cream is stable for 24 months after the date of manufacture.32

In vitro, at concentrations of 10, 50, or 250 ng/mL, oxiconazole is stable in plasma for 24 hours at 20°C or up to 5 months at -20°C.15

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