Ketoconazole 2% Shampoo is an antifungal shampoo specially against yeasts and Dermatophytes. It`s used for prophylaxis and treatment of seborrheic dermatitis and pityriasis versicolor.
Packaging: 100ml PE Bottle
Ketoconazole
Introduction
Ketoconazole, a synthetic azole antifungal agent, is an imidazole derivative.
Uses
Dermatophytoses and Cutaneous Candidiasis
Ketoconazole is used topically for the treatment of tinea corporis, tinea cruris, and tinea pedis caused by Epidermophyton floccosum, Trichophyton mentagrophytes, or T. rubrum. The drug also is used topically for the treatment of cutaneous candidiasis caused by Candida albicans. Ketoconazole also has been used effectively for the topical treatment of tinea manuum caused by Trichophyton and tinea corporis caused by Microsporum. 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.
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. 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, although other antifungal agents (e.g., ciclopirox olamine, butenafine hydrochloride, tolnaftate, undecylenic acid) also can be effective in the treatment of these infections. While topical antifungals usually are effective for the treatment of uncomplicated tinea manuum and tinea pedis, 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 (onychomycosis).
Clinical studies indicate that ketoconazole 2% cream generally is effective when used once daily for the treatment of tinea corporis, tinea cruris, tinea pedis, or cutaneous candidiasis. 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. 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, tinea pedis, and cutaneous candidiasis. 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).
Pityriasis (Tinea) Versicolor
Ketoconazole 2% cream or 2% shampoo is used topically for the treatment of pityriasis (tinea) versicolor, a superficial infection caused by Malassezia furfur (Pityrosporum orbiculare or P. ovale). 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%). 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. 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. A successful response was attained in 73% of those who received a 3-day regimen of once-daily application of the 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. The difference in efficacy between the 2 shampoo regimens was not statistically significant.
Seborrheic Dermatitis and Dandruff
Ketoconazole 2% cream is effective when used alone for the topical treatment of seborrheic dermatitis. The drug has reduced Malassezia ovalis (Pityrosporum ovale) cell counts in affected treated areas, and has improved manifestations of the dermatitis (e.g., scaling, pruritus, erythema).
Ketoconazole 2% shampoo has been used for the topical treatment of seborrheic dermatitis. In addition, following response to treatment, a prophylactic regimen (e.g., once-weekly application of the 2% shampoo) can effectively prevent relapse.
Ketoconazole also is used topically as a 1% shampoo for the reduction of scaling due to dandruff.
Other Uses
Ketoconazole 2% cream has also 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).
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. However, in rabbits, ketoconazole has generally been ineffective for the topical treatment of Aspergillus fumigatus keratitis. or C. albicans corneal infections. Commercially available ketoconazole 2% cream should not be applied to the eye.
Dosage and Administration
Administration
Ketoconazole is applied topically to the skin as a 2% cream. The cream should not be applied to the eye nor administered intravaginally. Ketoconazole is applied topically to hair or skin as a 2% shampoo or to the hair as a 1% shampoo.
Dosage
Dermatophytoses and Cutaneous Candidiasis
For the treatment of tinea corporis, tinea cruris, or tinea pedis, a sufficient amount of ketoconazole 2% topical cream should be applied and rubbed gently into the affected and surrounding areas of skin. The manufacturer recommends that ketoconazole 2% cream be applied once daily, but the cream also has been applied twice daily and there is some evidence that twice-daily application may occasionally be more effective for the treatment of tinea corporis or tinea cruris.
Although clinical improvement and relief of symptoms usually occur within the first week of therapy, 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. If clinical improvement does not occur after the recommended treatment period, the diagnosis should be reevaluated. Patients with chronic moccasin-type (dry-type) tinea pedis may require more prolonged therapy.
Pityriasis (Tinea) Versicolor
For the topical treatment of pityriasis (tinea) versicolor, a sufficient amount of ketoconazole 2% cream should be applied and rubbed gently into affected and surrounding areas once daily for 2 weeks. 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. A single application of ketoconazole 2% shampoo should be sufficient, although once-daily application for 3 days also has been used.
If clinical improvement does not occur after the recommended treatment period, the diagnosis should be reevaluated. Pityriasis (tinea) versicolor may give rise to hyperpigmented or hypopigmented patches on the trunk that may extend to the neck, arms, and upper thighs. Treatment of the infection may not immediately result in restoration of pigment to the affected sites. Normalization of pigment following successful therapy is variable and may take months, depending on individual skin type and incidental sun exposure. Although pityriasis (tinea) versicolor is not contagious, it may recur because the organism that causes the disease is part of the normal skin flora.
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 the affected areas twice daily. Topical therapy with the drug generally is continued for 4 weeks or until clinical clearing. If clinical improvement is not evident after 4 weeks of therapy, the diagnosis should be reevaluated.
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. Application should be repeated every 3 or 4 days for up to 8 weeks as needed or as directed by a clinician. Thereafter, the 1% shampoo should be used as needed to control dandruff.
Adverse Effects
Topically applied ketoconazole appears to have a low order of toxicity and is generally well tolerated. Adverse effects have been reported in up to 5% of patients receiving ketoconazole 2% cream and have consisted principally of local reactions such as severe irritation, pruritus, and stinging. A painful allergic reaction, consisting of localized swelling and inflammation, occurred in at least one patient receiving ketoconazole 2% cream and contact dermatitis occurred in another.
In several studies evaluating the potential of topical ketoconazole for causing dermal irritation, contact sensitization, or phototoxic or photoallergenic reactions in healthy adults, topical application of ketoconazole 2% cream caused mild transient erythema in some individuals, but did not cause contact sensitization of the delayed hypersensitivity type, irritation, phototoxicity, or photocontact sensitization.
Contact dermatitis has been reported following topical application of imidazole-derivative azole antifungals (e.g., clotrimazole, econazole, miconazole, oxiconazole, sulconazole, tioconazole). Cross-sensitization appears to occur among the imidazole derivatives; however, cross-sensitivity appears to be unpredictable. The fact that patients with contact sensitivity to one imidazole-derivative azole antifungal may be sensitive to other similar drugs should be considered.
Although hepatotoxicity has occurred during treatment with oral ketoconazole, it is unlikely that this adverse effect would occur with ketoconazole 2% cream since the drug does not appear to be appreciably absorbed following topical application to skin.
Adverse effects reported in patients receiving topical ketoconazole 2% as a shampoo applied to the skin include pruritus, application site reaction, and dry skin. Adverse effects reported in patients receiving ketoconazole 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. In some patients with permanently waved (“permed”) hair, use of ketoconazole 2% shampoo resulted in loss of the curl.
Precautions and Contraindications
Patients receiving topical ketoconazole therapy should be instructed to use the medication 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. Patients should also be instructed to contact their clinician if signs or symptoms of irritation or sensitization occur. If a reaction suggesting sensitivity or chemical irritation occurs during treatment with ketoconazole cream or shampoo, the drug should be discontinued.
Patients should be advised to avoid contact of ketoconazole shampoo with the eyes since irritation may occur.
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. 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.
Ketoconazole cream or shampoo is contraindicated in individuals with known hypersensitivity to the drug or any ingredient in the respective formulation. Commercially available ketoconazole 2% cream is intended for topical application to the skin only and should not be applied to the eye nor administered intravaginally. The 1 and 2% shampoos also are intended for topical application and should not be applied to the eye; if contact with the eye(s) occurs, rinse thoroughly with water.
Pediatric Precautions
Safety and efficacy of ketoconazole 2% cream or shampoo in children have not been established. Topical ketoconazole 2% cream has been used without unusual adverse effect in a limited number of children 2 days to 12 years of age. Safety and efficacy of ketoconazole 1% shampoo for self-medication in children younger than 12 years of age have not been established.
Mutagenicity and Carcinogenicity
In vitro studies using ketoconazole in a microbial system (i.e., Ames test) have not shown the drug to be mutagenic. 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. There was no evidence of carcinogenicity in a long-term feeding study in mice and rats.
Pregnancy and Lactation
Pregnancy
Ketoconazole 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). 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. 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. Ketoconazole 2% cream or shampoo should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. Pregnant women considering self-medication with the 1% shampoo should consult a clinician first before using the preparation.
Lactation
Since it is not known whether ketoconazole is distributed into milk following topical application, ketoconazole 2% cream should be used with caution in nursing women.1 Although ketoconazole 2% shampoo is not detected in plasma following chronic application, the shampoo should be used with caution in nursing women. Nursing women reconsidering self-medication with the 1% shampoo should consult a clinician before using the preparation.
Drug Interactions
Antiviral Agents
The clinical importance has not been determined, but ketoconazole and acyclovir have shown dose-dependent, synergistic, antiviral activity against herpes simplex virus types 1 and 2 in in vitro replication studies. Ketoconazole and vidarabine showed interference, indifference, or antagonism in vitro against these viruses.
Mechanism of Action
Ketoconazole is usually fungistatic in action, but may be fungicidal at high concentrations after prolonged incubation or against very susceptible organisms.
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. 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). 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. The mechanism(s) of action of topical ketoconazole in the treatment of dandruff has not been fully determined. The drug is active against Pityrosporum ovale, 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.
Spectrum
Ketoconazole is active against most pathogenic fungi, including dermatophytes and yeasts. The drug also has in vitro activity against some gram-positive bacteria, including Staphylococcus aureus, S. epidermidis, enterococci, Nocardia, and Actinomadura. 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).
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. In addition, currently available in vitro tests may not accurately reflect the in vivo susceptibility of some fungi (especially Candida).
Ketoconazole is active in vitro against Epidermophyton floccosum, Microsporum audouini, M. canis, M. gypseum, Trichophyton mentagrophytes, T. rubrum, and T. tonsurans. 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. In vitro on a weight basis, ketoconazole’s activity against dermatophytes appears to be similar to that of butoconazole, clotrimazole, econazole, miconazole, or tioconazole. Ketoconazole is also active in vitro against Malassezia furfur (Pityrosporum orbiculare) and M. ovalis (P. ovale).
A wide range of ketoconazole MIC values has been reported for Candida. 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.
For further information on the spectrum of activity of ketoconazole,
Pharmacokinetics
Absorption
Ketoconazole does not appear to be appreciably absorbed systemically following topical application to skin. In one study in healthy adults with intact skin, ketoconazole was not detected (lower detection limit of assay: 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). In one study, ketoconazole was not detected in plasma of patients receiving topical application of ketoconazole 2% shampoo 4–10 times weekly for 6 months, or in patients receiving ketoconazole 2% shampoo 2–3 times weekly for an average of 16 months (range: 3–26 months). Following topical application of 80 mg of ketoconazole 2% cream to the intact or abraded skin of beagles once daily for 28 days, ketoconazole was not detected in plasma (lower detection limit of the method used to assay: 2 ng/mL). 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 detection limit of assay: 5 ng/mL). In an in vitro model using human skin, ketoconazole was retained in the stratum corneum and the 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. Following a single topical application of ketoconazole 2% shampoo, substantial amounts of the drug were detected in hair 12 hours after application; however only 5% of the applied ketoconazole was detected in hair keratin. Following repeated (twice weekly for 2 months) application of ketoconazole 2% shampoo, 20% of the applied dose was detected in hair keratin.
Small amounts of ketoconazole are absorbed systemically when the drug is administered intravaginally. 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.
For information on absorption following oral administration and on the distribution and elimination of ketoconazole, see Pharmacokinetics in Ketoconazole 8:14.08.
Chemistry
Ketoconazole, a synthetic azole antifungal agent, is an imidazole derivative. Ketoconazole is structurally related to other imidazole-derivative azole antifungal agents (e.g., butoconazole, clotrimazole, econazole, miconazole, oxiconazole, sulconazole, tioconazole). Ketoconazole occurs as a white to slightly beige powder and is practically insoluble in water, having a solubility of 40 mcg/mL at 23°C, and is relatively insoluble in alcohol at 23°C. The drug has pKas of 2.9 and 6.5. For topical use, ketoconazole is commercially available as a cream in an aqueous base. Ketoconazole also is commercially available as a shampoo, which is an aqueous suspension of the drug containing a detergent and an emulsifying agent.