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Clotrimazole and Betamethasone (Topical)


VA CLASSIFICATION
Primary: DE250

Commonly used brand name(s): Lotriderm; Lotrisone.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antifungal-corticosteroid (topical){01}{13}{14}
Note: Clotrimazole is a broad-spectrum antifungal agent. {01} {13}



Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Tinea corporis (treatment){11}{12}{13}{14}
Tinea cruris (treatment) or{11}{12}{13}{14}
Tinea pedis (treatment){11}{12}{13}{14}—Clotrimazole and betamethasone dipropionate combination is indicated [as a secondary agent] {08} in the topical treatment of tinea corporis (ringworm of the body), tinea cruris (jock itch; ringworm of the groin), and tinea pedis (athlete's foot; ringworm of the foot), [accompanied by inflammation] {02} {14}, caused by Epidermophyton floccosum (Acrothesium floccosum) , Microsporum canis , Trichophyton rubrum , and Trichophyton mentagrophytes . {01} {11} {12} {13} {14}
—The use of clotrimazole and betamethasone dipropionate combination has been shown to provide greater benefit than either clotrimazole or betamethasone dipropionate alone {01} {02} {13} [during the first few days of treatment or for as long as inflammation persists, except on the palms of the hands and soles of the feet. After this time, USP medical experts recommend the use of plain clotrimazole or other topical antifungal agents] . {08}

[Candidiasis, cutaneous (treatment)]1—Clotrimazole and betamethasone dipropionate combination is used as a secondary agent in the topical treatment of cutaneous candidiasis (moniliasis), accompanied by inflammation, caused by Candida albicans (Monilia albicans) {08}.

—Not all species or strains of a particular organism may be susceptible to clotrimazole.

Unaccepted
Since corticosteroids may cause thinning of the skin and telangiectasia when used on the face or in intertriginous areas (e.g., axilla, genitals, perineum, groin, between the toes), clotrimazole and betamethasone dipropionate combination is not recommended for use in these areas for longer than a few days. {08}

Clotrimazole is not effective against bacteria, protozoa, or viruses. {02}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Clotrimazole: 344.85 {10} {13}
    Betamethasone dipropionate: 504.59 {10} {13}

Mechanism of action/Effect:

Clotrimazole—Fungistatic {13}; may be fungicidal {13}, depending on concentration. Inhibits biosynthesis of ergosterol or other sterols, damaging the fungal cell wall membrane and altering its permeability. As a result, leakage of intracellular phosphorus compounds with accompanying breakdown of cellular nucleic acids and accelerated potassium efflux occurs {13}. Clotrimazole also inhibits biosynthesis of triglycerides and phospholipids by fungi. In addition, it inhibits oxidative and peroxidative enzyme activity, resulting in intracellular buildup of toxic concentrations of hydrogen peroxide, which may contribute to deterioration of subcellular organelles and cellular necrosis. {01} {03}

Betamethasone dipropionate—Mechanism of betamethasone dipropionate's dermatological action is unclear. However, corticosteroids diffuse across cell membranes and complex with specific cytoplasmic receptors. These complexes then enter the cell nucleus, bind to DNA (chromatin), and stimulate transcription of messenger RNA (mRNA) and subsequent protein synthesis of various enzymes thought to be ultimately responsible for the anti-inflammatory effects. {01} {02} {04} Betamethasone dipropionate is effective in treating inflamed dermatoses because of its anti-inflammatory, antipruritic, and vasoconstrictive actions. {13} {14}

Absorption:

Clotrimazole—Minimal systemic absorption following topical application to skin {13}. Concentration of clotrimazole was shown to be 100 mcg per cm 3 in the stratum corneum, 0.5 to 1 mcg per cm 3 in the stratum reticulare, and 0.1 mcg per cm 3 in the subcutaneous tissue 6 hours following topical application of 1% clotrimazole cream and 1% clotrimazole topical solution to intact, acutely inflamed skin. {01} {03} {13}

Betamethasone dipropionate—May be absorbed systemically from normal intact skin {13}. Inflammation and/or other dermatologic pathology increases percutaneous absorption of topically applied corticosteroids, and absorption is significantly increased by use of occlusive dressings {13}. Other factors that augment absorption include the specific type of vehicle {13}, reduced integrity of the epidermal barrier {13}, higher corticosteroid potency, use over an extensive surface area, and prolonged use {13}. Children may absorb proportionately larger amounts of topically applied corticosteroids and are thus more susceptible to systemic toxicity. {01} {02} {04} {13}

Protein binding:

Betamethasone dipropionate (absorbed)—Bound to plasma proteins in varying degrees. {01} {13}

Biotransformation:

Betamethasone dipropionate (unabsorbed)—Metabolized mostly in the skin. {01} {02} {04}

Betamethasone dipropionate (absorbed)—Metabolized in a manner similar to that of systemically absorbed corticosteroids {13}. Metabolism is primarily hepatic {13}, mostly to inactive metabolites. Fluorinated compounds are more slowly metabolized in the skin and thus tend to be systemically absorbed to a greater extent. {01} {02} {04}

Peak serum concentration:

Clotrimazole—Application of C 14-labeled clotrimazole to intact or diseased skin under occlusive dressing for 6 hours did not yield measurable quantities (with a lower detection limit of 0.001 mcg per mL) of radioactive material in the sera of humans. {14}

Elimination:
    Renal {13}—Absorbed betamethasone dipropionate excreted via the kidneys, mainly as inactive metabolites. {01} {02} {04}
    Biliary/fecal—Some topically applied corticosteroids and their metabolites also excreted in the bile. {01} {02} {04} {13}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to other imidazoles or corticosteroids may be sensitive to this medication also. {01} {11} {13} {14}

Carcinogenicity/Mutagenicity

Animal and in vitro studies have not been done to evaluate the carcinogenic or mutagenic potential of clotrimazole and betamethasone dipropionate combination. {01} {11} {13}


Clotrimazole

An 18-month oral dosing study in rats has not shown that clotrimazole is carcinogenic. {01} {03} {11} {13}

Studies in Chinese hamsters, given clotrimazole in five oral doses of 100 mg per kg of body weight (mg/kg) prior to testing, have shown no mutagenic effects in the spermatophore chromosomes. {01} {03} {11} {13}


Pregnancy/Reproduction
Fertility—
Animal and in vitro studies with clotrimazole and betamethasone dipropionate combination have not been done to evaluate impairment of fertility. {01} {02} {11} {13}


Clotrimazole

Studies in rats and mice, given clotrimazole orally in doses of 50 to 120 mg/kg, have shown that clotrimazole causes impairment of mating. {01} {13}


Pregnancy—
Adequate and well-controlled teratogenicity studies with clotrimazole and betamethasone dipropionate combination have not been done in humans. {01} {02} {03} {11} {13} {14}


Clotrimazole

Studies in humans given clotrimazole intravaginally during the second and third trimesters have not shown that clotrimazole causes adverse effects on the fetus. {01} {02} {03}

Studies in rats, given clotrimazole intravaginally in doses of up to 100 mg/kg, have not shown that clotrimazole causes adverse effects on the fetus. {11} {13} Studies in rats and mice, given clotrimazole orally in doses of 50 to 120 mg/kg, have shown that clotrimazole causes embryotoxicity, decreased litter size and number of viable young, and decreased pup survival to weaning. {11} {13} However, studies in mice, rabbits, and rats, given clotrimazole orally in doses of 200, 180, and 100 mg/kg, respectively, have not shown that clotrimazole is teratogenic. {01} {03} {11} {13}



Betamethasone dipropionate

Topical corticosteroid-containing preparations should not be used on extensive surface areas, in large amounts, or for prolonged periods of time in pregnant patients. {01} {02} {11} {13} {14}

Studies in animals have shown that corticosteroids are generally teratogenic when administered systemically, even at relatively low doses. {11} {13} In addition, the more potent corticosteroids have been shown to be teratogenic following dermal application in animals. {11} {13}

FDA Pregnancy Category C. {01} {02} {11} {13}


Breast-feeding

It is not known whether clotrimazole or betamethasone dipropionate, applied topically, is distributed into human breast milk. {11} {13} {14} However, risk-benefit must be considered since clotrimazole and betamethasone dipropionate may be absorbed systemically following topical application. In addition, systemic corticosteroids are distributed into breast milk and may cause unwanted effects, such as growth suppression, in the infant. {01} {02} {03} {04}

Pediatrics

Appropriate studies on the relationship of age to the effects of this medicine have not been performed in children up to 12 years of age. Safety and efficacy have not been established {11} in children up to 12 years of age {13} {14}.


Betamethasone dipropionate:

Children may absorb proportionately larger amounts of topically applied corticosteroids than mature patients {13} {14}. Children may thus be more susceptible to topical corticosteroid-induced hypothalamic-pituitary-adrenal (HPA) axis suppression and Cushing's syndrome because of larger surface-area-to-body-weight ratio. {11} {13} {14} HPA axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. {11} {13} {14} Therefore, topical administration of corticosteroids in children should be limited to the least amount that is effective. {11} {13} {14} Chronic corticosteroids therapy may interfere with the growth and development of children. {01} {02} {04} {11} {13} {14}

As a general rule, pediatric therapy continuing for longer than 2 weeks and consisting of doses in excess of one daily application of betamethasone (base) 0.05%, a high-potency corticosteroid, should be carefully evaluated by the physician. This is especially important if medication is applied to more than 5 to 10% of the body surface or if an occlusive dressing {14} is used. A tight-fitting diaper or one covered with plastic pants may constitute an occlusive dressing. {01} {02} {04}



Geriatrics


No information is available on the relationship of age to the effects of clotrimazole and betamethasone combination in geriatric patients.


Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Adrenal function as assessed by corticotropin (ACTH) stimulation{13}{14} or measurement of plasma cortisol or urinary-free cortisol{13}{14} and
Hypothalamic-pituitary-adrenal (HPA) axis function    (may be decreased if significant absorption of betamethasone dipropionate occurs, especially in children {02} {04} {13} {14})


Blood glucose concentrations and
Urine glucose concentrations    (may be increased because of intrinsic hyperglycemic activity of betamethasone dipropionate {02} {04} {13} {14})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Bacterial infections of the skin{14}    (corticosteroids are not recommended for use in untreated bacterial infections {14})


Diaper dermatitis{13} or
Stasis dermatitis or other skin diseases with impaired circulation{14}    (topical corticosteroids are not recommended for use in diaper dermatitis)

    (suitable precautions should be taken when using topical corticosteroids in patients with stasis dermatitis or other skin diseases with impaired circulation)


» Herpes simplex{14} or
» Vaccinia{14} , eczema vaccinatum, varicella{14} , or other viral infections of the skin    (corticosteroids may accelerate the spread of viral infections {02})


Sensitivity to clotrimazole{13}{14} , betamethasone{13}{14} , or other imidazoles{13}{14} or corticosteroids{13}{14}
» Tubercular infections of the skin{14}    (corticosteroids may exacerbate or reactivate tubercular infections {02} {14})




Side/Adverse Effects

Note: Side/adverse effects may be more pronounced when this medication is used with an occlusive dressing {13} {14}; also, they may be more severe with fluorinated corticosteroids such as betamethasone. {02} {04} {13} {14}
Since topically applied corticosteroids may be absorbed systemically, systemic effects may occur, especially with prolonged use {13} {14}. The risk of adrenal suppression increases with the potency of the corticosteroid, the size of the area of application, and the duration of therapy. However, serious side/adverse effects with dermatological use are unlikely. {02} {04} {13} {14}
If skin irritation or hypersensitivity occurs, treatment with clotrimazole and betamethasone dipropionate combination should be discontinued. {01} {13} {14}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Hypersensitivity (blistering{13}{14} , burning{13}{14} , itching{13}{14} , peeling{13}{14} , dryness{13}{14} , redness{13}{14} , or other signs of skin irritation{13}{14} not present before therapy{01}{02}{04})
    
stinging{14}
    
urticaria{14} (hives)

Incidence rare
    
Paresthesia{14} (numbness of the hands and feet)
    
rash{14}
    
secondary infection{13}{14}
    
swelling{14}

With prolonged use
    
Acne or oily skin{13}{14}
    
allergic contact dermatitis{13}{14} (rash)
    
folliculitis{13}{14} (pus in the hair follicles)
    
hypopigmentation{13}{14} (white spots)
    
increased hair growth, especially on the face and body{13}{14}
    
increased loss of hair, especially on the scalp
    
perioral dermatitis{13}{14} (redness and scaling around the mouth)
    
reddish purple lines on arms, face, legs, trunk, or groin{13}{14}
    
skin atrophy{13}{14} (thinning of skin with easy bruising)
{02}{04}    
skin maceration{13} (softening of the skin)





Overdose
Overdose is minimal due to the limited amount of clotrimazole absorbed topically from the skin. However, betamethasone, with excessive and prolonged topical use, can suppress the pituitary and adrenal function, which could result in secondary adrenal insufficiency, hypercorticism or Cushing's disease {14}. Acute hypercorticism symptoms are usually reversible. Chronic toxicity may require slow withdrawal of the corticosteroid {14}.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing

Treatment of overdose
There is no known specific antidote to clotrimazole and betamethasone overdose.

Specific treatment—Symptomatic treatment may be given {14}. Acute toxicity with corticosteroids is usually reversible {14}. Chronic toxicity with corticosteroids may require a slow withdrawal of the drug {14}. Treat electrolyte imbalance; electrolyte replacement may be required {14}.

Supportive care—Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Clotrimazole and Betamethasone (Topical) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
  Conditions affecting use, especially:
Allergies to imidazoles or corticosteroids {13} {14}

Pregnancy—Not recommended in pregnancy {14} because of possibility of teratogenicity, especially when used on extensive surface areas, in large amounts, or for prolonged periods of time





Breast-feeding—May cause systemic effects, such as growth suppression, in infants





Use in children—May cause HPA axis suppression, Cushing's syndrome, intracranial hypertension, or growth suppression {13} {14}

Other medical problems, especially eczema vaccinatum, herpes simplex, tubercular infections of the skin, vaccinia, varicella, or other viral infections of the skin

Proper use of this medication
Before applying, washing affected area with soap and water, and drying thoroughly

» Not for ophthalmic use {13} {14}

To use
» Checking with physician before using medication on other skin problems

Applying a thin layer of medication to affected area(s) and surrounding skin; rubbing in gently and thoroughly
» Not applying occlusive dressing {13} {14} over this medication unless directed to do so by physician; wearing loose-fitting clothing {13} when using on inguinal area; avoiding tight-fitting diapers and plastic pants on diaper area of children

» Compliance with full course of therapy; not using more often or for longer than directed by physician; excessive use on thin skin areas may result in skin atrophy and stretch marks {14}

» Proper dosing
Missed dose: Applying as soon as possible; not applying if almost time for next dose

» Proper storage

Precautions while using this medication
Checking with physician if no improvement is observed within 1 week for tinea corporis or tinea cruris and 2 weeks for tinea pedis {13} {14}; redness and itching should improve within 3 to 5 days

Using hygienic measures to help cure infection and to help prevent reinfection:

For tinea pedis
Carefully drying feet, especially between toes, after bathing

Not wearing socks made from wool or synthetic materials; wearing clean, cotton socks and changing them daily or more often if feet perspire excessively

Wearing well-ventilated shoes or sandals

Using a bland, absorbent powder or an antifungal powder liberally between toes, on feet, and in socks and shoes once or twice daily; using the powder after cream has been applied and has disappeared into the skin; not using the powder as sole therapy for your fungal infection

For tinea cruris
Carefully drying inguinal area after bathing

Not wearing underwear that is tight-fitting or made from synthetic materials; wearing loose-fitting cotton underwear instead

Using a bland, absorbent powder or an antifungal powder liberally once or twice daily; using the powder after cream has been applied and has disappeared into the skin; not using the powder as sole therapy for your fungal infection

For tinea corporis
Carefully drying the body after bathing

Avoiding excess heat and humidity if possible; keeping moisture from accumulating on affected areas of the body

Wearing well-ventilated clothing

Using a bland, absorbent powder or an antifungal powder liberally once or twice daily; using the powder after cream has been applied and has disappeared into the skin; not using the powder as sole therapy for your fungal infection
» Patients with diabetes: Betamethasone may rarely cause hyperglycemia and glucosuria {13}, especially with severe diabetes and use of large amounts; checking with physician before changing diet or dosage of antidiabetic medication


Side/adverse effects
Signs of potential side effects, especially hypersensitivity; stinging; urticaria; paresthesia; rash; secondary infection; swelling; and long-term effects, including acne or oily skin; allergic contact dermatitis; folliculitis; hypopigmentation; increased hair growth on face and body; increased hair loss on scalp; perioral dermatitis; reddish purple lines on arms, face, legs, trunk, or groin; skin atrophy; and skin maceration


General Dosing Information
As a general rule, pediatric therapy continuing for longer than 2 weeks and consisting of doses in excess of one daily application of betamethasone (base) 0.05%, a high-potency corticosteroid, should be carefully evaluated by the physician. This is especially important if medication is applied to more than 5 to 10% of the body surface or if an occlusive dressing is used. A tight-fitting diaper or one covered with plastic pants may constitute an occlusive dressing. {01} {02} {04}

The use of clotrimazole and betamethasone cream, in adults, should not be continued beyond 4 weeks {13} {14}.

Do not use this medication in the eyes. {01} {13} {14}

Therapeutic efficacy of the corticosteroid depends on drug release from the vehicle, solubilization of the drug at the skin surface, and its subsequent percutaneous absorption through the outer barrier layer of the epidermis (stratum corneum). The corticosteroid can thus reach the site of action in the living epidermis and/or the dermis. {02}

Factors influencing product selection include skin hydration, site, and severity of infection, age of patient, whether the lesion is moist or dry, and method of application. {02}

This medication contains a high-potency corticosteroid that is fluorinated {13} and has a substituted 17-hydroxyl group. Fluorinated corticosteroids containing substituted 17-hydroxyl groups are resistant to local metabolism in the skin. Repeated application results in a cumulative depot effect in the skin, which may lead to a prolonged duration of action, increased risk of systemic absorption, and increased side effects. {02} {04}

Since corticosteroids may cause thinning of the skin and telangiectasia when used on the face or in intertriginous areas (e.g., axilla, genitals, perineum, groin, between the toes), clotrimazole and betamethasone dipropionate combination is not recommended for use in these areas for longer than a few days. After this time, USP medical experts recommend the use of plain clotrimazole or other topical antifungal agents. {08}

Use of occlusive dressings should be avoided, {11} {13} {14} since they provide conditions that favor the growth of yeast and release of its irritating endotoxin. Occlusive dressings also promote increased hydration of the stratum corneum and increased absorption. An oleaginous ointment, a thin film of polyethylene, a bandage, a tight-fitting diaper, plastic pants, or tape may constitute an occlusive dressing. {01} {02}

If skin irritation or hypersensitivity occurs, treatment with clotrimazole and betamethasone dipropionate combination should be discontinued. {01} {13} {14}


Topical Dosage Forms

CLOTRIMAZOLE AND BETAMETHASONE DIPROPIONATE CREAM USP

Usual adult and adolescent dose
Tinea corporis; or
Tinea cruris
Topical, to the affected skin and surrounding area(s), two times a day, morning and evening {01} {11} for 2 weeks {13} {14}.

Tinea pedis
Topical, to the affected skin and surrounding area(s), two times a day, morning and evening {01} {11} for 4 weeks {13} {14}.


Usual pediatric dose
Infants and children up to 12 years of age—Safety and efficacy have not been established. {11} {13} {14}
Children 12 years of age and over—See Usual adult and adolescent dose.

Strength(s) usually available
U.S.—


1% of clotrimazole and 0.05% of betamethasone (base) (Rx) [Lotrisone{11}{13} (purified water) (mineral oil) (white petrolatum) (cetearyl alcohol) (ceteareth-30) (propylene glycol) (sodium phosphate monobasic) (phosphoric acid) (benzyl alcohol)]

Canada—


1% of clotrimazole and 0.05% of betamethasone (base) (Rx) [Lotriderm{12}{14} (purified water) (mineral oil) (white petrolatum) (cetearyl alcohol) (ceteareth-30) (propylene glycol) (sodium phosphate monobasic) (phosphoric acid) (benzyl alcohol)]

Packaging and storage:
Store between 2 and 30 °C (36 and 86 °F) {13} {14}, unless otherwise specified by manufacturer. Store in a collapsible tube or tight container. Protect from freezing.

Auxiliary labeling:
   • For external use only {13} {14}.
   • Continue medication for full time of treatment.
   • Do not use in the eyes {13} {14}.

Additional information:
Clotrimazole and betamethasone dipropionate cream is available in a hydrophilic emollient cream base. {01} {11} {12} {13} {14}



Revised: 06/14/1999



References
  1. Lotrisone package insert, Schering (U.S.), PDR 1988: 1923-24.
  1. Nystatin and Triamcinolone (Topical) mgh, USP DI 1989.
  1. Clotrimazole (Topical) mgh, USP DI 1989.
  1. Adrenocorticoids (Topical) mgh, USP DI 1989.
  1. Naftifine (Topical) mgh, USP DI 1990 (proposed).
  1. Econazole (Topical) mgh, USP DI 1988.
  1. Open.
  1. Panel comments, Clotrimazole and Betamethasone (Topical) mgh, 2/10/89.
  1. Panel comments, Naftifine (Topical), 1/13/89.
  1. USAN 1990: 74, 147.
  1. PDR-91, p. 2003, Lotrisone, Schering.
  1. CPS-91, p. 673, Lotriderm, Schering.
  1. Lotrisone (Schering). In: PDR Physicians' desk reference. 52nd ed. Montvale, NJ: Medical Economics Company; 1998. p. 2646-47.
  1. Lotriderm (Schering). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialities. 33rd ed. Ottawa: Canadian Pharmacists Association; 1998. p. 910.
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