Ketoconazole, a synthetic azole antifungal agent, is an imidazole derivative.1, 3, 4, 5, 6, 11, 23, 32, 72, 105, 106, 110
Ketoconazole is used topically as a 2% cream for the treatment of tinea corporis, tinea cruris, and tinea pedis caused by Epidermophyton floccosum , Trichophyton mentagrophytes , or T. rubrum .1, 2, 25, 27, 28, 56, 58, 59, 60, 61, 62, 66, 78, 79, 110 The drug also has been used effectively for the topical treatment of tinea manuum† caused by Trichophyton 2, 25, 58, 59, 60, 61, 62 and tinea corporis caused by Microsporum †.2, 25, 59 Like other imidazole derivatives (e.g., clotrimazole, econazole, miconazole, oxiconazole, sulconazole) and ciclopirox olamine, ketoconazole 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 .2, 2, 59
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.80, 81, 82, 84 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,81, 85 although other antifungals (e.g., ciclopirox olamine, butenafine hydrochloride, tolnaftate, undecylenic acid) also can be effective in the treatment of these infections.80, 81, 82, 83, 84 While topical antifungals usually are effective for the treatment of uncomplicated tinea manuum and tinea pedis,80, 81, 82, 83, 84 an oral antifungal usually is necessary for the treatment of hyperkeratotic areas on the palms and soles,81, 84 for chronic moccasin-type (dry-type) tinea pedis,78, 80, 81, 83 and for the treatment of tinea unguium (onychomycosis).80, 81, 82, 83, 84
Clinical studies indicate that ketoconazole 2% cream generally is effective when used once daily for the treatment of tinea corporis, tinea cruris, or tinea pedis.25, 27, 28, 60, 61, 66 However, in one controlled study, twice-daily application of the cream was more effective than once-daily application for the topical treatment of tinea corporis and tinea cruris.62 In several controlled studies, ketoconazole 2% cream used twice daily was as effective as clotrimazole 1% cream used twice daily for the treatment of tinea corporis, tinea cruris, or tinea pedis.2, 25, 58, 59 Ketoconazole 2% cream has been effective in a few patients for the topical treatment of tinea pedis extending beyond interdigital areas (e.g., moccasin-type tinea pedis).79
Ketoconazole is used topically as a 2% cream for the treatment of cutaneous candidiasis caused by C. albicans .1, 2, 25, 58, 59, 67, 68, 69, 110 Like other imidazole derivatives (e.g., clotrimazole, econazole, miconazole, oxiconazole, sulconazole) and ciclopirox olamine, ketoconazole has an advantage over some other topical antifungals (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 .2
Clinical studies indicate that ketoconazole 2% cream generally is effective when used once daily for the treatment of cutaneous candidiasis.25, 68 In several controlled studies, ketoconazole 2% cream used twice daily was as effective as clotrimazole 1% cream used twice daily for the treatment of cutaneous candidiasis.2, 25, 58, 59
Ketoconazole is used topically as a 2% cream or 2% shampoo for the treatment of pityriasis (tinea) versicolor, a superficial infection caused by or presumed to be caused by Malassezia furfur .1, 2, 25, 26, 63, 72, 97, 110
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%).80, 83, 87, 88 However, an oral antifungal (e.g., itraconazole, ketoconazole) may be indicated, with or without a topical agent, in patients who have extensive or severe infections or who fail to respond to or have frequent relapses with topical therapy.
Clinical studies indicate that ketoconazole 2% cream generally is effective when used once daily for the treatment of pityriasis (tinea) versicolor.25, 26, 63 Safety and efficacy of ketoconazole 2% shampoo for the topical treatment of pityriasis (tinea) versicolor was evaluated in a double-blind, placebo-controlled study in patients with moderately severe, mycologically confirmed infections.72, 97 A successful response was attained in 73% of those who received a 3-day regimen of once-daily application of 2% ketoconazole shampoo, 69% of those who received a single application of the shampoo, and 5% of those who received placebo; the mycologic clearance rates were 84, 78, and 11%, respectively.97 The difference in efficacy between the 2 shampoo regimens was not statistically significant.97
Seborrheic Dermatitis and Dandruff
Ketoconazole is used topically for the treatment of seborrheic dermatitis, including seborrheic dermatitis of the scalp.1, 12, 42, 43, 44, 67, 71, 73, 76, 98, 99, 101, 103, 105, 106, 107, 108, 109 Ketoconazole also is used topically for self-medication for the reduction of flaking, scaling, and itching associated with dandruff.100, 104
Ketoconazole 2% cream is effective when used alone for the topical treatment of seborrheic dermatitis of the face, scalp, chest, or back.12, 42, 43, 44, 67, 71, 76 The drug has reduced Malassezia ovalis ( Pityrosporum ovale ) cell counts in affected treated areas, and has improved manifestations of dermatitis (e.g., scaling, pruritus, erythema).43, 67, 70, 71, 73, 98
Ketoconazole 2% foam is used for the treatment of seborrheic dermatitis in immunocompetent adults and children 12 years of age or older.106, 109 In a phase 3 randomized, double-blind study in adults and children 12 years of age or older with mild, moderate, or severe seborrheic dermatitis involving the scalp, face, chest, or ears, ketoconazole 2% foam twice daily for 4 weeks was more effective than vehicle foam and noninferior to ketoconazole 2% cream.106, 109 The foam improved manifestations of dermatitis (erythema, scaling, induration).106, 109
Ketoconazole 2% gel is used for the treatment of seborrheic dermatitis in immunocompetent adults and children 12 years of age or older.77, 105, 107, 108 In a phase 3 randomized, double-blind study in adults and children 12 years of age or older with moderate to severe seborrheic dermatitis, ketoconazole 2% gel once daily for 14 days was more effective than gel vehicle and resulted in improvements in manifestations of dermatitis (scaling, erythema, pruritus).105, 107
Ketoconazole 1% shampoo is used for self-medication to reduce flaking, scaling, and itching associated with dandruff.100, 104
Ketoconazole 2% shampoo has been used for the topical treatment of scalp seborrheic dermatitis and dandruff†.76, 98, 99, 101 Following response to treatment, a prophylactic regimen (e.g., once-weekly application of the 2% shampoo) has prevented relapse.98
Ketoconazole 2% cream has been used with good results in combination with a topical corticosteroid (beclomethasone dipropionate or clobetasone butyrate) and an antibacterial agent (fusidate sodium) for the treatment of a variety of dermatoses that frequently involve fungal or bacterial superinfections (e.g., atopic dermatitis, diaper rash, eczema, folliculitis, impetigo, intertrigo, lichenoid dermatitis, psoriasis)†.13, 14, 15, 16, 17, 18, 19, 20
An extemporaneously prepared ophthalmic suspension containing ketoconazole 2% has been used with some success in a limited number of patients for the topical treatment of fungal keratitis† caused by Alternaria , Aspergillus , Fusarium , or Mycelia sterilia.29 However, in rabbits, ketoconazole has generally been ineffective for the topical treatment of Aspergillus fumigatus keratitis†30 or C. albicans corneal infections†.31, 72, 103, 104, 105, 106 Commercially available ketoconazole cream, foam, gel, and shampoo should not be applied to the eye .1
For other uses of ketoconazole, see 8:14.08
Ketoconazole is applied topically to the skin as a 2% cream,1, 110 foam,106 gel,105 or shampoo.72, 97
Ketoconazole is applied topically to the hair and scalp as a 1% shampoo.100, 104 The drug also has been applied topically to hair† and scalp† as a 2% shampoo.76, 98, 99, 101, 103
Ketoconazole topical cream, foam, gel, and shampoo are for external use only.1, 72, 104, 105, 106 These topical preparations should not be applied to the eyes1, 72, 104, 105, 106 and should not be administered orally105, 106 or intravaginally.56, 57, 105, 106
If contact with eyes, mouth, or vagina occurs, the exposed areas should be rinsed thoroughly with water.104, 106
Fire, flame, and/or smoking should be avoided during and immediately after application of ketoconazole 2% foam or gel.105, 106 (See Cautions: Precautions and Contraindications.)
For the topical treatment of tinea corporis, tinea cruris, or tinea pedis, a sufficient amount of ketoconazole 2% cream should be applied and rubbed gently into the affected and surrounding area of skin once daily.1, 110 The cream also has been applied twice daily,2, 25, 58, 59, 60, 62, 66, 79 and there is some evidence that a twice-daily regimen may occasionally be more effective than a once-daily regimen for the treatment of tinea corporis or tinea cruris.25, 62
Although clinical improvement and relief of symptoms usually occur within the first week of therapy,1, 27 tinea corporis and tinea cruris generally should be treated for 2 weeks and tinea pedis should be treated for 6 weeks to reduce the possibility of recurrence.1, 110 If clinical improvement does not occur after the recommended treatment period, the diagnosis should be reevaluated.1, 110 Patients with chronic moccasin-type (dry-type) tinea pedis may require more prolonged therapy.66, 79
For the topical treatment of cutaneous candidiasis, a sufficient amount of ketoconazole 2% cream should be applied and rubbed gently into the affected and surrounding area of skin once daily.1, 110 The cream also has been applied twice daily.2, 25, 58, 59
Although clinical improvement may be seen earlier, cutaneous candidiasis should be treated for 2 weeks to reduce the possibility of recurrence.1, 110 If clinical improvement does not occur after the recommended treatment period, the diagnosis should be reevaluated.1, 110
For the topical treatment of pityriasis (tinea) versicolor, a sufficient amount of ketoconazole 2% cream should be applied and rubbed gently into the affected and surrounding area once daily for 2 weeks.1, 110
Alternatively, ketoconazole 2% shampoo should be applied to the damp skin of the affected area and a wide margin surrounding this area and lathered; after 5 minutes, the area should be rinsed with water.72 A single application of ketoconazole 2% shampoo should be sufficient,72, 97 although once-daily application for 3 days also has been used.72, 97
If clinical improvement does not occur after the recommended treatment period, the diagnosis should be reevaluated.1, 110 Pityriasis (tinea) versicolor may give rise to hyperpigmented or hypopigmented patches on the trunk that may extend to the neck, arms, and upper thighs.72 Treatment of the infection may not immediately result in restoration of pigment to the affected sites.72 Normalization of pigment following successful therapy is variable and may take months, depending on individual skin type and incidental sun exposure.72 Although pityriasis (tinea) versicolor is not contagious, it may recur because the organism that causes the disease is part of the normal skin flora.72
Seborrheic Dermatitis and Dandruff
For the treatment of seborrheic dermatitis, a sufficient amount of ketoconazole 2% topical cream should be applied and rubbed gently into affected areas twice daily for 4 weeks or until clinical clearing.1, 12, 42, 43, 44, 67, 71 If clinical improvement is not evident after 4 weeks of therapy, the diagnosis should be reevaluated.1
For the treatment of seborrheic dermatitis in adults and children 12 years of age or older, a sufficient amount of ketoconazole 2% topical foam should be applied to affected areas twice daily for 4 weeks.106, 109
The can containing ketoconazole 2% foam should be held upright and a small amount of the foam sprayed into the cap of the can or other cool surface.106 The foam should not be dispensed directly onto the affected areas or onto hands since the foam will begin to melt immediately on contact with warm skin.106 If the fingers are warm, they should be rinsed in cold water and dried before handling the foam.106 Using the fingertips, small amounts of the foam should be massaged gently onto affected areas until the foam disappears and the entire affected area has been treated.106
For the treatment of seborrheic dermatitis in adults and children 12 years of age or older, ketoconazole 2% topical gel should be applied sparingly in a thin film to affected areas once daily for 2 weeks.105, 107, 108
Hands should be washed before and after applying the gel.105 Sunscreen or cosmetics should not be applied to the affected area until at least 20 minutes after application of ketoconazole gel.105 Patients should not wash the affected area for at least 3 hours after application of the gel.105, 108
For self-medication in the control of dandruff in adults and children older than 12 years of age, a sufficient amount of ketoconazole 1% shampoo should be applied to thoroughly wet hair, generously lathered, rinsed thoroughly, and then application, lathering, and rinsing repeated.104 Application should be repeated every 3 or 4 days for up to 8 weeks as needed or as directed by a clinician.104 Thereafter, the 1% shampoo should be used as needed to control dandruff.104
For the treatment of scalp seborrheic dermatitis and dandruff†, ketoconazole 2% shampoo has been used to wash the hair and scalp 2 or 3 times weekly for 2-4 weeks.76, 98, 99, 101 After a response was obtained, the shampoo has been used once weekly every other week to prevent relapse.98
Topically applied ketoconazole appears to have a low order of toxicity and is generally well tolerated.1, 2, 24, 25, 73, 97, 98, 99, 100, 101
Adverse effects have been reported in up to 5% of patients receiving topical ketoconazole 2% cream1, 2, 110 and have consisted principally of local reactions such as severe irritation, pruritus, and stinging.1, 2, 25, 26, 58, 59, 60, 61, 110 A painful allergic reaction, consisting of localized swelling and inflammation, occurred in at least one patient receiving ketoconazole 2% cream.1, 56
Rarely, ketoconazole 2% cream or one of its excipients (e.g., sodium sulfite, prophylene glycol) has been associated with contact dermatitis.1, 61, 110 Topical application of ketoconazole 2% foam may cause contact sensitization or photoallergenicity.106
Contact dermatitis has been reported following topical application of other imidazole-derivative azole antifungals (e.g., clotrimazole, econazole, miconazole, oxiconazole, sulconazole, tioconazole).89, 90, 91, 92, 93, 94 Cross-sensitization appears to occur among the imidazole derivatives; however, cross-sensitivity appears to be unpredictable.89, 90, 91, 92, 93, 94 The fact that patients with contact sensitivity to one imidazole-derivative azole antifungal may be sensitive to other similar drugs should be considered.90, 91, 92, 93, 94
Some formulations of ketoconazole 2% cream contain sodium sulfite, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.110 The overall prevalence of sulfite sensitivity in the general population is unknown, but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.110
The most frequently reported adverse effects in patients using topical ketoconazole 2% foam include burning and application site reactions.106, 109 Application site reactions reported in up to 1% of patients include dryness, erythema, irritation, paresthesia, pruritus, rash, and warmth.106
The most frequently reported adverse effects in patients using topical ketoconazole 2% gel are burning at the application site and headache.105, 107, 108 In studies evaluating the potential of topical ketoconazole 2% gel for causing dermal irritation, contact sensitization, or phototoxic or photoallergenic reactions, the gel caused irritation, but did not cause contact sensitization, phototoxicity, or photoallergenicity.105
Following topical application of ketoconazole 2% shampoo to the skin, adverse effects include pruritus, application site reaction, and dry skin.72 Adverse effects reported following topical application of ketoconazole 2% shampoo to the scalp include increased hair loss, irritation, abnormal hair texture, scalp pustules, dry skin, pruritus, and oiliness or dryness of the hair and scalp.72, 100, 101 In some patients with permanently waved (“permed”) hair, use of ketoconazole 2% shampoo resulted in loss of the curl.72, 101
Although hepatotoxicity, decreased testosterone concentrations, and decreased corticotropin (ACTH)-induced corticosteroid concentrations have been reported with oral ketoconazole,32, 105, 110 these adverse effects have not been reported with topical ketoconazole105, 110 and are unlikely since the drug does not appear to be appreciably absorbed following topical application to skin.2, 56, 57
Precautions and Contraindications
Ketoconazole 2% cream, gel, and shampoo are contraindicated in individuals with known hypersensitivity to the drug or any ingredient in the formulation.1, 72, 105, 110
Patients should be instructed to contact their clinician if signs or symptoms of irritation or sensitization occur.56, 57, 104 If a reaction suggesting sensitivity or chemical irritation occurs during treatment with ketoconazole cream, foam, gel, or shampoo, the drug should be discontinued.1, 72, 105, 106, 110
Patients should be instructed to use topical ketoconazole for the full, prescribed treatment period, even if symptoms improve, and to contact their clinician if their skin condition does not improve after a full course of therapy.56, 57, 104
Ketoconazole 2% gel or foam is used only for the treatment of seborrheic dermatitis.105, 106 The safety and efficacy of the foam or gel for the treatment of fungal infections have not been established.105, 106
Commercially available ketoconazole 2% cream, foam, or gel is intended for topical application to the skin only and should not be applied to the eyes1, 105, 106 and should not be administered intravaginally.56, 57, 105, 106 The 1 and 2% shampoos also are intended for topical application only and should not be applied to the eyes;72, 104 if contact with the eyes occurs, the eyes should be rinsed thoroughly with water.104
Patients receiving ketoconazole 1% shampoo for self-medication of dandruff should be advised to not use the shampoo if the scalp is broken or inflamed and to avoid contact with the eyes.104 They also should be advised to discontinue the shampoo and contact a clinician if rash occurs or the condition worsens or does not improve within 2-4 weeks since these may be signs of a serious condition.104
Ketoconazole 2% foam and gel are flammable.105, 106 Patients should be advised to avoid fire, flame, and/or smoking during and immediately after application of the gel or foam.105, 106
Safety and efficacy of ketoconazole 2% cream have not been established in children.1, 110 Topical ketoconazole 2% cream has been used without unusual adverse effect in a limited number of children 2 days to 12 years of age.15, 17
Safety and efficacy of ketoconazole 2% foam or gel have not been established in children younger than 12 years of age.105, 106
Safety and efficacy of ketoconazole 2% shampoo have not been established in children.72 Safety and efficacy of ketoconazole 1% shampoo for self-medication have not been established in children younger than 12 years of age.104
Mutagenicity and Carcinogenicity
In vitro studies using ketoconazole in a microbial system (i.e., Ames test) have not shown the drug to be mutagenic.1, 32, 72, 105, 110 In addition, there was no evidence of mutagenicity in any stage of germ cell development in a dominant lethal mutation test in mice who received single oral doses of ketoconazole as high as 80 mg/kg.1, 32, 72, 105, 110 There was no evidence of carcinogenicity in a long-term feeding study in mice and rats.1, 32, 72, 105, 106, 110
Ketoconazole 2% cream, foam, gel, or shampoo should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1, 72, 105, 106, 110 Pregnant women considering self-medication with ketoconazole 1% shampoo should consult a clinician before using the preparation.104
Ketoconazole has been teratogenic and has caused webbing of the feet and absence of toes in the fetus when given orally to pregnant rats in a dosage of 80 mg/kg daily (10 times the maximum recommended human oral dosage).1, 32, 72, 105, 106, 110 The drug has also been found to be embryotoxic in rats when given during the first trimester of pregnancy and has caused dystocia when given during the third trimester.32 Although these effects may reflect a particular sensitivity of female rats to ketoconazole (maternal toxicity), there are no adequate and controlled studies to date using ketoconazole in pregnant women.1, 32, 72, 105, 106, 110
Since it is not known whether ketoconazole is distributed into milk following topical application, the manufacturers of ketoconazole 2% cream recommend that a decision be made to discontinue nursing or the cream.1, 110 The manufacturers of ketoconazole 2% foam and gel state the drugs should be used with caution in nursing women.105, 106 Although ketoconazole 2% shampoo is not detected in plasma following chronic application, the shampoo should be used with caution in nursing women.72 Nursing women considering self-medication with the 1% shampoo should consult a clinician before using the preparation.104
Ketoconazole is usually fungistatic in action, but may be fungicidal at high concentrations after prolonged incubation or against very susceptible organisms.3, 5, 21, 34, 48, 49, 50, 52, 53, 54, 55
Like other imidazole derivatives, ketoconazole presumably exerts its antifungal activity by altering cellular membranes, resulting in increased membrane permeability, secondary metabolic effects, and growth inhibition.1, 21, 23, 32, 48, 49, 50, 51, 52, 55, 105, 106, 110 Although the exact mechanism of action of ketoconazole has not been fully determined, it has been suggested that the fungistatic activity of the drug may result from interference with ergosterol synthesis probably via inhibition of C-14 demethylation of sterol intermediates (e.g., lanosterol).1, 21, 34, 49, 50, 51, 55, 105, 106, 110 Like some other imidazole derivatives (e.g., miconazole), the fungicidal activity of ketoconazole at high concentrations may result from a direct physiochemical effect of the drug on the fungal cell membrane, but the direct effect of ketoconazole on cell membranes appears to be substantially less than that of miconazole.3, 55
The mechanism(s) of action of topical ketoconazole in the treatment of dandruff has not been fully determined.72 The drug is active against Pityrosporum ovale ,72, 73, 74, 75, 76 a yeast-like fungus that is part of the normal flora of the scalp. Although it has been suggested that P. ovale may be associated with the development of dandruff, a definite causal relationship between the organism and this condition has not been established.73, 74, 75, 76
Ketoconazole is active against most pathogenic fungi, including dermatophytes and yeasts.1, 2, 3, 10, 22, 32, 40, 72, 110 The drug also has in vitro activity against some gram-positive bacteria, including Staphylococcus aureus ,3, 22 S. epidermidis ,22 enterococci,22 Nocardia ,22 and Actinomadura .3, 22 Although the clinical importance is unknown, ketoconazole also appears to have some in vitro activity against herpes simplex virus types 1 and 2 (HSV-1 and -2).38
Results of in vitro ketoconazole susceptibility tests for fungi are method dependent, and MIC values vary substantially depending on the culture medium used, pH, presence of serum, and inoculum size.4, 6, 7, 8, 10, 22, 35, 36, 54 In addition, currently available in vitro tests may not accurately reflect the in vivo susceptibility of some fungi (especially Candida ).6, 7, 22
Ketoconazole is active in vitro against Epidermophyton floccosum ,1, 4, 6, 10, 22, 32, 40, 72, 110 Microsporum audouini ,1, 10, 22, 32, 40, 72, 110 M. canis ,1, 4, 10, 22, 32, 40, 72, 110 M. gypseum ,1, 4, 10, 22, 32, 40, 72, 110 Trichophyton mentagrophytes ,1, 4, 10, 22, 32, 40, 72, 110 T. rubrum ,1, 4, 10, 22, 32, 40, 72, 110 and T. tonsurans .1, 4, 10, 22, 32, 72, 110, 40 The MIC90 (minimum inhibitory concentration of the drug at which 90% of strains tested are inhibited) of ketoconazole for these dermatophytes is generally 0.25-2 mcg/mL.4, 6, 8 In vitro on a weight basis, ketoconazole's activity against dermatophytes appears to be similar to that of butoconazole,35 clotrimazole,35, 36 econazole,35, 36, 37 miconazole,4, 8, 10, 35, 36 or tioconazole.36, 37 Ketoconazole is also active in vitro against Malassezia furfur 1, 39, 45, 72, 105, 106, 110 and M. ovalis ( Pityrosporum. ovale ).39, 40, 72, 105
A wide range of ketoconazole MIC values has been reported for Candida .4, 5, 6, 7, 8, 10, 22, 36, 40 In some in vitro studies, the MIC90 of ketoconazole for C. albicans , C. parapsilosis , and C. tropicalis was 1-16 mcg/mL; however, in other studies, these organisms required ketoconazole concentrations of 25 mcg/mL or greater for in vitro inhibition.4, 5, 6, 7, 8, 10, 22
For further information on the spectrum of activity of ketoconazole, see Spectrum in Ketoconazole 8:14.08.
Strains of C. albicans resistant to ketoconazole have been isolated from patients who received the drug.35, 46, 47, 64 C. albicans isolated from several patients with chronic mucocutaneous candidiasis were reportedly resistant to ketoconazole and most other currently available imidazole derivatives.35, 64
Ketoconazole does not appear to be appreciably absorbed systemically following topical application to skin or scalp.1, 2, 24, 25, 56, 63, 72, 105, 106, 110
In one study in healthy adults with intact skin, ketoconazole was not detected (lower limits of detection 5 ng/mL) in blood during the 72-hour period immediately following a single topical application to the chest, back, and arms of 10 g of ketoconazole 2% cream (200 mg of ketoconazole).1, 2, 24, 110 Following topical application of 80 mg of ketoconazole 2% cream to intact or abraded skin of beagles once daily for 28 days, ketoconazole was not detected in plasma (lower limits of detection 2 ng/mL).1, 110 In an in vitro model using human skin, ketoconazole was retained in the stratum corneum and boundary of the stratum corneum and stratum granulosum for up to 16 hours following topical application of radiolabeled ketoconazole cream; little or no drug appeared to penetrate into deeper layers of the epidermis.56, 63
In a study in patients with moderate to severe seborrheic dermatitis, topical application of ketoconazole 2% foam (3 g of ketoconazole) twice daily for 4 weeks resulted in plasma ketoconazole concentrations that were less than 6 ng/mL in 75% of patients; the maximum plasma concentration reported was 11 ng/mL.106
In a study in patients with severe seborrheic dermatitis (1-14% of body surface area), topical application of ketoconazole 2% gel once daily for 2 weeks (daily dose 0.05-3.47 g), the mean peak plasma concentration was 1.35 ng/mL on day 7 and 0.8 ng/mL on day 14.105
Ketoconazole was not detected in plasma of patients who shampooed with ketoconazole 2% shampoo 4-10 times weekly for 6 months or 2-3 times weekly for an average of 16 months (range: 3-26 months).72 Following topical application of ketoconazole 2% shampoo (50 mg/kg) daily for 28 days to intact or abraded skin of rabbits (drug remained on skin for 1 hour before being washed away), ketoconazole was not detected in plasma (lower limits of detection 5 ng/mL).72 Following a single topical application of ketoconazole 2% shampoo, substantial amounts of the drug were detected on hair 12 hours after application; however only 5% of the applied ketoconazole was detected in hair keratin.103 Following repeated (twice weekly for 2 months) application of ketoconazole 2% shampoo, 20% of the applied dose was detected in hair keratin.103
Small amounts of ketoconazole are absorbed systemically when the drug is administered intravaginally.24 Following intravaginal administration of 400 mg of ketoconazole as a vaginal suppository in healthy women, peak plasma ketoconazole concentrations ranged from undetectable to 20.7 ng/mL.24, 56
For information on absorption following oral administration and information on the distribution and elimination of ketoconazole, see Pharmacokinetics in Ketoconazole 8:14.08.
Ketoconazole, a synthetic azole antifungal agent, is an imidazole derivative.1, 3, 4, 5, 6, 11, 23, 32, 72, 105, 106, 110 Ketoconazole is structurally related to other imidazole-derivative azole antifungal agents (e.g., butoconazole, clotrimazole, econazole, miconazole, oxiconazole, sulconazole, tioconazole).3, 4, 5, 6, 11, 23
Ketoconazole occurs as a white to slightly beige powder and is soluble in acids;32 it has a solubility of 40 mcg/mL in water at 23°C, and is relatively insoluble in alcohol at 23°C.56 For topical use, ketoconazole is commercially available as a cream in an aqueous base,1, 110 a thermolabile hydroalcoholic foam,106 and an anhydrous gel.105 Ketoconazole also is commercially available as a shampoo, which is an aqueous suspension of the drug containing a detergent and an emulsifying agent.72
Ketoconazole 2% topical cream should be stored at a temperature of 20-25°C110 or 15-30°C,1 depending on the manufacturer. The cream should not be stored at high temperatures (e.g., warmer than 37°C), since creams generally separate at these temperatures,48 and should not be frozen.48
Ketoconazole 2% foam should be stored at a temperature of 20-25°C and should not be refrigerated or frozen.106 The foam is flammable and should not be stored in direct sunlight or exposed to heat or temperatures exceeding 49°C.106 The container should not be punctured and/or incinerated.106
Ketoconazole 2% gel should be stored at a temperature of 25°C, but may be exposed to temperatures ranging from 15-30°C.105
Ketoconazole 2% shampoo should be stored at temperatures not exceeding 25°C and should be protected from light;72 the 1% shampoo should be stored between 2-30°C and should be protected from light and freezing.104
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Topical | Cream | 2%* | ||
Foam | 2% | |||
Gel | 2% | |||
Shampoo | 1% | Nizoral® A-D | ||
2%* | Ketoconazole Shampoo, | |||
Nizoral® |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Taro Pharmaceuticals. Ketoconazole cream, 2% prescribing information. Brampton, Ontario; 2002 Nov.
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60. Swanson NA. A double-blind randomized comparative trial of once- and twice-daily ketoconazole 2% cream and placebo in the treatment of tinea pedis. Janssen Pharmaceutica clinical research report. Piscataway, NJ; 1984 Sep.
61. Jolly HW, Greer D. Double-blind comparison of two doses of 2% ketoconazole cream (R41,400) in the treatment of chronic and acute tinea pedis. Janssen Pharmaceutica clinical research report No. N 31512. Piscataway, NJ; 1983 Mar.
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104. McNeil Consumer Healthcare. Nizoral® A-D (ketoconazole) 1% shampoo patient information. Fort Washington, PA; 2002 Dec 18.
105. Barrier Therapeutics, Inc. Xolegel® (ketoconazole) 2% gel prescribing information. Princeton, NJ; 2006 Jul.
106. Stiefel Laboratories, Inc. Extina® (ketoconazole) 2% foam prescribing information. Coral Gables, FL; 2007 Jun.
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