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  • CLASSES

    Combinations of Corticosteroids with Antifungals

    DEA CLASS

    Rx

    DESCRIPTION

    Topical product containing betamethasone, a high potency corticosteroid, and clotrimazole, an imidazole antifungal
    Indicated to treat cutaneous tinea infections
    Can cause reversible hypothalamic-pituitary-adrenal (HPA) axis suppression

    COMMON BRAND NAMES

    Lotrisone

    HOW SUPPLIED

    Clotrimazole, Betamethasone/Clotrimazole, Betamethasone Dipropionate/Lotrisone Topical Cream: 1-0.05%
    Clotrimazole, Betamethasone/Clotrimazole, Betamethasone Dipropionate/Lotrisone Topical Lotion: 1-0.05%

    DOSAGE & INDICATIONS

    For the treatment of tinea corporis, tinea cruris, and tinea pedis infections caused by Epidermophyton floccosum, Trichophyton mentagrophytes, or Trichophyton rubrum).
    NOTE: The efficacy for the treatment of infections caused by zoophilic dermatophytes (e.g., Microsporum canis†) has not been established. Several cases of treatment failure have been reported with betamethasone; clotrimazole cream.
    Topical dosage (cream or lotion)
    Adults and Adolescents >= 17 years

    Apply sparingly to the affected skin twice per day. Recommended treatment duration is 1 week (maximum of 2 weeks) for tinea corporis and tinea cruris infections, and 2 weeks (maximum of 4 weeks) for tinea pedis infections.

    For the secondary treatment of topical candidiasis† with inflammation due to susceptible strains of Candida sp.† including Candida albicans†.
    Topical dosage (cream)
    Adults and Adolescents >= 17 years

    Apply sparingly to the affected skin and surrounding areas twice per day.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    No maximum dosage information is available.

    Elderly

    No maximum dosage information is available.

    Adolescents

    >= 17 years: No maximum dosage information is available.
    < 17 years: Use not recommended.

    Children

    Use not recommended.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment is needed.

    Renal Impairment

    No dosage adjustment is needed.

    ADMINISTRATION

    Topical Administration

    For topical dermatologic use only. Not for ophthalmic, oral, or vaginal use.
    Wash hands before and after application. Use gloves if required by universal precautions.
    Apply sparingly in a thin film and rub gently into affected area(s) of clean, dry skin. Restrict application to the affected areas and try to avoid normal surrounding skin.
    Patients with tinea corporis or tinea cruris who fail to respond to treatment after 1 week should be re-evaluated; do not use longer than 2 weeks.
    Patients with tinea pedis who fail to respond to treatment after 2 weeks should be re-evaluated; do not use longer than 4 weeks.
    Avoid occlusive dressings. Instruct patients not to bandage, cover, or wrap area in any way that may be occlusive, unless directed by prescriber.

    Cream/Ointment/Lotion Formulations

    The amount of cream needed to cover a certain skin area can be calculated. A 1 gram application of cream covers 100 cm2 of skin. The entire skin surface of the average size adult will be covered by 30 grams of topical cream.

    STORAGE

    Lotrisone:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Do not use clotrimazole; betamethasone for more than a few days on the face or in intertriginous areas (e.g., axilla, genitals, perineum) due to the potential of corticosteroid-induced skin thinning or telangiectasias. However, clotrimazole; betamethasone is used for up to two weeks to treat the groin area for tinea cruris and up to four weeks to treat athlete's foot (tinea pedis).

    Pregnancy

    There are no adequate, well-controlled studies to evaluate the topical application of clotrimazole; betamethasone in pregnant women. In animal studies, betamethasone was shown to be teratogenic in rabbits (i.e., umbilical hernias, cephalocele, cleft palate) when administered intramuscularly at a dose of 0.05 mg/kg/day during organogenesis; however, data did not allow for relevant comparisons between the exposures observed in rabbits and exposures expected in humans following topical administration. Topical corticosteroids, including betamethasone, should not be used in large amounts, on large areas, or for prolonged periods in pregnant women. Guidelines recommend mild to moderate potency agents over potent corticosteroids, which should be used in short durations. Fetal growth restriction and a significantly increased risk of low birth weight have been reported with the use of potent or very potent topical corticosteroids during the third trimester, particularly when using more than 300 grams. Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals.[62792] Only administer clotrimazole; betamethasone during pregnancy if the benefit justifies the potential risks.[47219]

    Breast-feeding

    Data are limited regarding use of topical clotrimazole; betamethasone during breast-feeding is not known if these drugs are excreted in breast milk following topical administration. Because many drugs may be excreted in breast milk, clotrimazole; betamethasone should be used cautiously in women who are breast-feeding. It is not known whether topical administration of betamethasone could result in sufficient systemic absorption to produce detectable quantities in breast milk. However, most dermatologists stress that topical corticosteroids can be safely used during lactation and breast-feeding. If applied topically, care should be used to ensure the infant will not come into direct contact with the area of application, such as the breast. Increased blood pressure has been reported in an infant whose mother applied a high potency topical corticosteroid ointment directly to the nipples. Consider therapy with less-potent topical agents, like hydrocortisone or triamcinolone, in nursing mothers requiring long-term therapy with a topical corticosteroid. Clotrimazole topically to the skin is likely compatible; the site of infection, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative agent. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Peripheral vascular disease, skin abrasion

    Topical clotrimazole; betamethasone should be used with extreme caution in patients with peripheral vascular disease or other conditions causing poor circulation due to the risk of skin ulceration. Because corticosteroids can inhibit wound healing, clotrimazole; betamethasone should not be used in areas of skin abrasion.

    Azole antifungals hypersensitivity

    Clotrimazole; betamethasone should be used with caution in patients with azole antifungals hypersensitivity. Clotrimazole may exhibit a cross sensitivity with other azole derivatives such as itraconazole, fluconazole, ketoconazole, and miconazole.

    Children, growth inhibition, increased intracranial pressure, infants, neonates

    The use of clotrimazole; betamethasone is not recommended in neonates, infants, children, and adolescents less than 17 years of age. Administration of topical corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen. Pediatric patients may absorb proportionally larger amounts of topical corticosteroids due to a larger skin surface area to body weight ratio, and therefore, are more susceptible to developing systemic toxicity. Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing's syndrome, growth inhibition (linear growth retardation and delayed weight gain), and increased intracranial pressure have been reported in children receiving topical corticosteroids. In open-label studies, 17 of 43 (39.5%) evaluable pediatric patients (age 12 to 16 years) demonstrated adrenal suppression while using clotrimazole; betamethasone cream for treatment of tinea pedis. Safety of clotrimazole; betamethasone cream or lotion has not been established in the treatment of diaper dermatitis (diaper rash) in infants. If children are being treated in the diaper area, tight-fitting diapers or plastic pants should be avoided as these garments may act as an occlusive dressing and increase systemic absorption of the drug.

    Geriatric, skin atrophy

    Topical corticosteroid preparations including clotrimazole; betamethasone, may exacerbate pre-existing skin atrophy. Geriatric patients, due to the concomitant thinning of the skin that occurs with aging, may be at increased for this effect. It is recommended that topical corticosteroids be used with caution and under close monitoring in patients with skin atrophy. The use of lower potency topical corticosteroids may be necessary in some patients.

    Cataracts, glaucoma, ocular exposure

    Avoid ocular exposure to clotrimazole; betamethasone. If ocular exposure occurs, rinse eye thoroughly with water. Topical corticosteroid products increase the risk of posterior subcapsular cataracts and glaucoma. If visual symptoms occur, consider referral to an ophthalmologist for evaluation.

    ADVERSE REACTIONS

    Severe

    skin atrophy / Delayed / Incidence not known
    increased intracranial pressure / Early / Incidence not known
    papilledema / Delayed / Incidence not known
    ocular hypertension / Delayed / Incidence not known
    retinopathy / Delayed / Incidence not known

    Moderate

    edema / Delayed / 0-1.0
    contact dermatitis / Delayed / Incidence not known
    erythema / Early / Incidence not known
    Cushing's syndrome / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    hypothalamic-pituitary-adrenal (HPA) suppression / Delayed / Incidence not known
    growth inhibition / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    cataracts / Delayed / Incidence not known

    Mild

    skin irritation / Early / 0-2.0
    paresthesias / Delayed / 1.9-1.9
    xerosis / Delayed / 1.6-1.6
    infection / Delayed / 0-1.0
    rash / Early / 0-1.0
    acneiform rash / Delayed / Incidence not known
    miliaria / Delayed / Incidence not known
    hypertrichosis / Delayed / Incidence not known
    skin hypopigmentation / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    striae / Delayed / Incidence not known
    folliculitis / Delayed / Incidence not known
    headache / Early / Incidence not known

    DRUG INTERACTIONS

    Progesterone: (Moderate) Vaginal preparations of progesterone (e.g., Crinone, Endometrin, and Prochieve) should not be used with other intravaginal products (e.g., vaginal antifungals, such as clotrimazole, miconazole nitrate, terconazole, or tioconazole vaginal) as concurrent use may alter progesterone release and absorption from the vagina. Separate the times of administration to avoid the interaction. The manufacturers of Crinone and Prochieve indicate that other intravaginal products can be used as long as 6 hours has lapsed either before or after vaginal administration of progesterone. Endometrin is generally not recommended for use with other vaginal products (e.g., antifungal products) as this may alter progesterone release and absorption from the vaginal insert and the potential for interaction has not been formally assessed; use other vaginal products if medically necessary, but be aware that the response to Endometrin may be altered.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate, well-controlled studies to evaluate the topical application of clotrimazole; betamethasone in pregnant women. In animal studies, betamethasone was shown to be teratogenic in rabbits (i.e., umbilical hernias, cephalocele, cleft palate) when administered intramuscularly at a dose of 0.05 mg/kg/day during organogenesis; however, data did not allow for relevant comparisons between the exposures observed in rabbits and exposures expected in humans following topical administration. Topical corticosteroids, including betamethasone, should not be used in large amounts, on large areas, or for prolonged periods in pregnant women. Guidelines recommend mild to moderate potency agents over potent corticosteroids, which should be used in short durations. Fetal growth restriction and a significantly increased risk of low birth weight have been reported with the use of potent or very potent topical corticosteroids during the third trimester, particularly when using more than 300 grams. Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals.[62792] Only administer clotrimazole; betamethasone during pregnancy if the benefit justifies the potential risks.[47219]

    Data are limited regarding use of topical clotrimazole; betamethasone during breast-feeding is not known if these drugs are excreted in breast milk following topical administration. Because many drugs may be excreted in breast milk, clotrimazole; betamethasone should be used cautiously in women who are breast-feeding. It is not known whether topical administration of betamethasone could result in sufficient systemic absorption to produce detectable quantities in breast milk. However, most dermatologists stress that topical corticosteroids can be safely used during lactation and breast-feeding. If applied topically, care should be used to ensure the infant will not come into direct contact with the area of application, such as the breast. Increased blood pressure has been reported in an infant whose mother applied a high potency topical corticosteroid ointment directly to the nipples. Consider therapy with less-potent topical agents, like hydrocortisone or triamcinolone, in nursing mothers requiring long-term therapy with a topical corticosteroid. Clotrimazole topically to the skin is likely compatible; the site of infection, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative agent. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Clotrimazole; betamethasone cream has antifungal, antiinflammatory, vasoconstrictive, and antipruritic properties. The antifungal activity of clotrimazole is not affected by combination with betamethasone.
    Clotrimazole: Like other azole antifungals, clotrimazole exerts its effect by altering the fungal cell membrane. Clotrimazole inhibits ergosterol synthesis by interacting with 14-alpha demethylase, a cytochrome P-450 enzyme that is necessary for converting lanosterol to ergosterol, an essential component of the fungal cell membrane. Other antifungal effects of azole compounds have been proposed and include: inhibition of endogenous respiration, interaction with membrane phospholipids, and inhibition of transformation of yeasts to mycelial forms. Additional mechanisms may involve inhibition of purine uptake and impairment of either triglyceride and/or phospholipid biosynthesis. Fungi have demonstrated little resistance to clotrimazole. The drug is primarily active against a wide variety of fungi, yeast, dermatophytes, and certain gram positive bacteria.
    Betamethasone: Pharmacologic doses of betamethasone help to decrease inflammation by inhibiting the release of leukocytic acid hydrolases, preventing macrophage accumulation at the site of infection, interfering with leukocyte adhesion to the capillary wall, reducing capillary membrane permeability (thereby reducing edema), reducing complement components, inhibiting histamine and kinin release, and interfering with the formation of scar tissue. The antiinflammatory actions of corticosteroids are thought to involve phospholipase A2 inhibitory proteins, collectively called lipocortins. Lipocortins, in turn, control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of the precursor molecule arachidonic acid. Synthetic corticosteroids suppress the immune system by decreasing the function of the lymphatic system, reducing immunoglobulin and complement concentrations, precipitating lymphocytopenia, inhibiting the transport of immune complexes across the capillary membrane, and interfering with antigen-antibody binding.

    PHARMACOKINETICS

    Clotrimazole; betamethasone cream is administered topically.
    Clotrimazole: Small amounts of absorbed clotrimazole are metabolized in the liver and excreted in the bile.
    Betamethasone: Betamethasone binds weakly to plasma proteins, and only the unbound drug is active. Systemically absorbed corticosteroids distribute into the breast milk and cross the placenta. Topical preparations of betamethasone are metabolized in the skin. These inactive metabolites, as well as a small portion of unchanged drug are systemically absorbed and are excreted in the urine. The biological half-life of betamethasone is 35 to 54 hours.

    Topical Route

    Clotrimazole: There is little systemic absorption of clotrimazole following topical application to the skin.
    Betamethasone: The amount of betamethasone absorbed following topical application is dependent on the integrity of the skin at the application site. Absorption after topical application is increased in areas that have skin damage, inflammation, or occlusion, or in areas where the stratum corneum is thin such as the eyelids, genitalia, and face. Topical preparations distribute throughout the area of application.