CLOTRIMAZOLE AND BETAMETHASONE DIPROPIONATE- clotrimazole and betamethasone dipropionate cream 
Prasco Laboratories

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use clotrimazole and betamethasone dipropionate cream safely and effectively. See full prescribing information for clotrimazole and betamethasone dipropionate cream.

Clotrimazole and betamethasone dipropionate cream, 1%/0.05%, for topical use

Initial U.S. Approval: 1984

INDICATIONS AND USAGE

Clotrimazole and Betamethasone Dipropionate cream contains a combination of clotrimazole, an azole antifungal, and betamethasone dipropionate, a corticosteroid, and is indicated for the topical treatment of symptomatic inflammatory tinea pedis, tinea cruris, and tinea corporis due to Epidermophyton floccosum, Trichophyton mentagrophytes, and Trichophyton rubrum in patients 17 years and older. (1)

DOSAGE AND ADMINISTRATION

  • Tinea pedis: Apply a thin film to the affected skin areas twice a day for 2 weeks. (2)
  • Tinea cruris and tinea corporis: Apply a thin film to the affected skin area twice a day for 1 week. (2)
  • Clotrimazole and Betamethasone Dipropionate cream should not be used longer than 2 weeks in the treatment of tinea corporis or tinea cruris, and longer than 4 weeks in the treatment of tinea pedis. (2)
  • Do not use with occlusive dressings unless directed by a physician. (2)
  • Not for ophthalmic, oral or intravaginal use. (2)

DOSAGE FORMS AND STRENGTHS

Cream, 1%/0.05% (3)

Each gram of clotrimazole and betamethasone dipropionate cream contains 10 mg of clotrimazole and 0.643 mg of betamethasone dipropionate (equivalent to 0.5 mg of betamethasone) (3)

CONTRAINDICATIONS

None. (4)

WARNINGS AND PRECAUTIONS

  • Clotrimazole and Betamethasone Dipropionate cream can cause reversible HPA axis suppression with the potential for glucocorticosteroid insufficiency during and after withdrawal of the treatment. Risk factor(s) are: use of high-potency topical corticosteroid, use over a large surface area or to areas under occlusion, prolonged use, altered skin barrier, liver failure, and young age. Modify use should HPA axis suppression develop. (5.1, 8.4)
  • Pediatric patients may be more susceptible to systemic toxicity. (5.1, 8.4)
  • The use of clotrimazole and betamethasone dipropionate cream in the treatment of diaper dermatitis is not recommended. (5.2)

ADVERSE REACTIONS

Most common adverse reactions reported for clotrimazole and betamethasone dipropionate cream were paraesthesia in 1.9% of patients and rash, edema, and secondary infections each in less than 1% of patients. (6.1)


To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 6/2014

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Clotrimazole and Betamethasone Dipropionate cream is a combination of an azole antifungal and corticosteroid and is indicated for the topical treatment of symptomatic inflammatory tinea pedis, tinea cruris, and tinea corporis due to Epidermophyton floccosum, Trichophyton mentagrophytes, and Trichophyton rubrum in patients 17 years and older.

2 DOSAGE AND ADMINISTRATION

Treatment of tinea corporis or tinea cruris:

Treatment of tinea pedis:

Clotrimazole and Betamethasone Dipropionate cream is for topical use only. It is not for oral, ophthalmic, or intravaginal use.

3 DOSAGE FORMS AND STRENGTHS

Cream, 1%/0.05%. Each gram of clotrimazole and betamethasone dipropionate cream contains 10 mg of clotrimazole and 0.643 mg of betamethasone dipropionate (equivalent to 0.5 mg of betamethasone) in a white to off-white cream base.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Effects on Endocrine System

Clotrimazole and Betamethasone Dipropionate cream can cause reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency. This may occur during treatment or after withdrawal of treatment. Cushing's syndrome and hyperglycemia may also occur due to the systemic effect of corticosteroids while on treatment. Factors that predispose a patient to HPA axis suppression include the use of high-potency steroids, large treatment surface areas, prolonged use, use of occlusive dressing, altered skin barrier, liver failure, and young age.

Because of the potential for systemic corticosteroid effects, patients may need to be periodically evaluated for HPA axis suppression. This may be done by using the adrenocorticotropic hormone (ACTH) stimulation test.

In a small trial, clotrimazole and betamethasone dipropionate cream was applied using large dosages, 7 g daily for 14 days (BID) to the crural area of normal adult subjects. Three of the 8 normal subjects on whom clotrimazole and betamethasone dipropionate cream was applied exhibited low morning plasma cortisol levels during treatment. One of these subjects had an abnormal cosyntropin test. The effect on morning plasma cortisol was transient and subjects recovered 1 week after discontinuing dosing. In addition, 2 separate trials in pediatric subjects demonstrated adrenal suppression as determined by cosyntropin testing [see Use in Specific Populations (8.4)].

If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of application, or substitute with a less potent corticosteroid.

Pediatric patients may be more susceptible to systemic toxicity due to their larger skin-surface-to-body mass ratios [see Use in Specific Populations (8.4)].

5.2 Diaper Dermatitis

The use of clotrimazole and betamethasone dipropionate cream in the treatment of diaper dermatitis is not recommended.

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials common adverse reaction reported for clotrimazole and betamethasone dipropionate cream was paresthesia in 1.9% of patients. Adverse reactions reported at a frequency < 1% included rash, edema, and secondary infection.

6.2 Postmarketing Experience

Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following local adverse reactions have been reported with topical corticosteroids: itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, maceration of the skin, skin atrophy, striae, miliaria, capillary fragility (ecchymoses), telangiectasia, and sensitization (local reactions upon repeated application of product).

Adverse reactions reported with the use of clotrimazole are: erythema, stinging, blistering, peeling, edema, pruritus, urticaria, and general irritation of the skin.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic effects,

Pregnancy Category C

There are no adequate and well-controlled studies with clotrimazole and betamethasone dipropionate cream in pregnant women. Therefore, clotrimazole and betamethasone dipropionate cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

There have been no teratogenic studies performed in animals or humans with the combination of clotrimazole and betamethasone dipropionate. Corticosteroids are generally teratogenic in laboratory animals when administered at relatively low dosage levels.

Studies in pregnant rats with intravaginal doses up to 100 mg/kg (15 times the maximum human dose) revealed no evidence of fetotoxicity due to clotrimazole exposure.

No increase in fetal malformations was noted in pregnant rats receiving oral (gastric tube) clotrimazole doses up to 100 mg/kg/day during gestation Days 6 to 15. However, clotrimazole dosed at 100 mg/kg/day was embryotoxic (increased resorptions), fetotoxic (reduced fetal weights), and maternally toxic (reduced body weight gain) to rats. Clotrimazole dosed at 200 mg/kg/day (30 times the maximum human dose) was maternally lethal, and therefore, fetuses were not evaluated in this group. Also in this study, doses up to 50 mg/kg/day (8 times the maximum human dose) had no adverse effects on dams or fetuses. However, in the combined fertility, teratogenicity, and postnatal development study described above, 50 mg/kg clotrimazole was associated with reduced maternal weight gain and reduced numbers of offspring reared to 4 weeks.

Oral clotrimazole doses of 25, 50, 100, and 200 mg/kg/day (2-15 times the maximum human dose) were not teratogenic in mice. No evidence of maternal toxicity or embryotoxicity was seen in pregnant rabbits dosed orally with 60, 120, or 180 mg/kg/day (18-55 times the maximum human dose).

Betamethasone dipropionate has been shown to be teratogenic in rabbits when given by the intramuscular route at doses of 0.05 mg/kg. This dose is approximately one-fifth the maximum human dose. The abnormalities observed included umbilical hernias, cephalocele, and cleft palates.

Betamethasone dipropionate has not been tested for teratogenic potential by the dermal route of administration. Some corticosteroids have been shown to be teratogenic after dermal application to laboratory animals.

8.3 Nursing Mothers

Systemically administered corticosteroids appear in human milk and can suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids can result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when clotrimazole and betamethasone dipropionate cream is administered to a nursing woman.

8.4 Pediatric Use

The use of clotrimazole and betamethasone dipropionate cream in patients under 17 years of age is not recommended.

Adverse events consistent with corticosteroid use have been observed in pediatric patients treated with clotrimazole and betamethasone dipropionate cream. In open-label trials, 17 of 43 (39.5%) evaluable pediatric subjects (aged 12-16 years old) using clotrimazole and betamethasone dipropionate cream for treatment of tinea pedis demonstrated adrenal suppression as determined by cosyntropin testing. In another open-label trial, 8 of 17 (47.1%) evaluable pediatric subjects (aged 12-16 years old) using clotrimazole and betamethasone dipropionate cream for treatment of tinea cruris demonstrated adrenal suppression as determined by cosyntropin testing.

Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of HPA axis suppression when they are treated with topical corticosteroids. They are, therefore also at greater risk of adrenal insufficiency during and/or after withdrawal of treatment. Pediatric patients may be more susceptible than adults to skin atrophy, including striae, when they are treated with topical corticosteroids.

HPA axis suppression, Cushing's syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteroids [see Warnings and Precautions (5.1)].

Avoid use of clotrimazole and betamethasone dipropionate cream in the treatment of diaper dermatitis.

8.5 Geriatric Use

Clinical studies of clotrimazole and betamethasone dipropionate cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, greater sensitivity of some older individuals cannot be ruled out. The use of clotrimazole and betamethasone dipropionate cream under occlusion, such as in diaper dermatitis, is not recommended.

Postmarket adverse event reporting for clotrimazole and betamethasone dipropionate cream in patients aged 65 and above includes reports of skin atrophy and rare reports of skin ulceration. Caution should be exercised with the use of these corticosteroid-containing topical products on thinning skin.

11 DESCRIPTION

Clotrimazole and betamethasone dipropionate cream, 1%/0.05%, contains combinations of clotrimazole, an azole antifungal, and betamethasone dipropionate, a corticosteroid, for topical use.

Chemically, clotrimazole is 1–(o-chloro-α,α-diphenylbenzyl) imidazole, with the empirical formula C22H17CLN2, a molecular weight of 344.84, and the following structural formula:

Chemical Structure

Clotrimazole is an odorless, white crystalline powder, insoluble in water and soluble in ethanol.

Betamethasone dipropionate has 9-fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 17,21-dipropionate, with the empirical formula C28H37FO7, a molecular weight of 504.59, and the following structural formula:

Chemical Structure

Betamethasone dipropionate is a white to creamy-white, odorless crystalline powder, insoluble in water.

Each gram of clotrimazole and betamethasone dipropionate cream contains 10 mg clotrimazole and 0.643 mg betamethasone dipropionate (equivalent to 0.5 mg betamethasone), in a white to off-white, hydrophilic cream consisting of benzyl alcohol as a preservative, ceteareth-30, cetyl alcohol plus stearyl alcohol, mineral oil, phosphoric acid, propylene glycol, purified water, sodium phosphate monobasic monohydrate, and white petrolatum.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Clotrimazole is an azole antifungal [see Clinical Pharmacology (12.4)].

Betamethasone dipropionate is a corticosteroid. Corticosteroids play a role in cellular signaling, immune function, inflammation, and protein regulation; however, the precise mechanism of action for the treatment of tinea pedis, tinea cruris and tinea corporis is unknown.

12.2 Pharmacodynamics

Vasoconstrictor Assay:

Studies performed with clotrimazole and betamethasone dipropionate cream indicate that these topical combination antifungal/corticosteroids may have vasoconstrictor potencies in a range that is comparable to high-potency topical corticosteroids. However, similar blanching scores do not necessarily imply therapeutic equivalence.

12.3 Pharmacokinetics

Skin penetration and systemic absorption of clotrimazole and betamethasone dipropionate following topical application of clotrimazole and betamethasone dipropionate cream has not been studied.

The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin may increase percutaneous absorption of topical corticosteroids. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids [see Dosage and Administration (2)].

Once absorbed through the skin, the pharmacokinetics of topical corticosteroids are similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile.

12.4 Microbiology

Mechanism of Action:

Clotrimazole, an azole antifungal agent, inhibits 14-α-demethylation of lanosterol in fungi by binding to one of the cytochrome P-450 enzymes. This leads to the accumulation of 14-α-methylsterols and reduced concentrations of ergosterol, a sterol essential for a normal fungal cytoplasmic membrane. The methylsterols may affect the electron transport system, thereby inhibiting growth of fungi.

Activity In Vitro and In Vivo:

Clotrimazole has been shown to be active against most strains of the following dermatophytes, both in vitro and in clinical infections, Epidermophyton floccosum, Trichophyton mentagrophytes, and Trichophyton rubrum [see Indications and Usage (1)].

Drug Resistance:

Strains of dermatophytes having a natural resistance to clotrimazole have not been reported. Resistance to azoles, including clotrimazole, has been reported in some Candida species.

No single-step or multiple-step resistance to clotrimazole has developed during successive passages of Trichophyton mentagrophytes.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

There are no adequate laboratory animal studies with either the combination of clotrimazole and betamethasone dipropionate or with either component individually to evaluate carcinogenesis.

Betamethasone was negative in the bacterial mutagenicity assay (Salmonella typhimurium and Escherichia coli) and in the mammalian cell mutagenicity assay (CHO/HGPRT). It was positive in the in vitro human lymphocyte chromosome aberration assay, and equivocal in the in vivo mouse bone marrow micronucleus assay.

Reproductive studies with betamethasone dipropionate carried out in rabbits at doses of 1.0 mg/kg by the intramuscular route and in mice up to 33 mg/kg by the intramuscular route indicated no impairment of fertility except for dose-related increases in fetal resorption rates in both species. These doses are approximately 5- and 38-fold the maximum human dose based on body surface areas, respectively.

In a combined study of the effects of clotrimazole on fertility, teratogenicity, and postnatal development, male and female rats were dosed orally (diet admixture) with levels of 5, 10, 25, or 50 mg/kg/day (approximately 1-8 times the maximum dose in a 60-kg adult based on body surface area) from 10 weeks prior to mating until 4 weeks postpartum. No adverse effects on the duration of estrous cycle, fertility, or duration of pregnancy were noted.

14 CLINICAL STUDIES

In clinical trials of tinea corporis, tinea cruris, and tinea pedis, subjects treated with clotrimazole and betamethasone dipropionate cream showed a better clinical response at the first return visit than subjects treated with clotrimazole cream. In tinea corporis and tinea cruris, the subject returned 3 to 5 days after starting treatment, and in tinea pedis, after 1 week. Mycological cure rates observed in subjects treated with clotrimazole and betamethasone dipropionate cream were as good as, or better than, in those subjects treated with clotrimazole cream. In these same clinical studies, patients treated with clotrimazole and betamethasone dipropionate cream showed better clinical responses and mycological cure rates when compared with subjects treated with betamethasone dipropionate cream.

16 HOW SUPPLIED/STORAGE AND HANDLING

Clotrimazole and betamethasone dipropionate cream is white to off-white and supplied in 15-gram (NDC 66993-898-15) and 45-gram tubes (NDC 66993-898-45), boxes of one. Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Rx only

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling (Patient Information)

Inform the patient of the following:

Manufactured for:
Prasco Laboratories
Mason, OH 45040, USA

Manufactured by:
Schering Plough Canada Inc., Pointe Claire, Quebec H9R 1B4, Canada

Revised: 6/2014

uspi-gmk5335A-cr-1406r001

Patient Information

Clotrimazole and betamethasone dipropionate cream, 1%/0.05%

Important information: Clotrimazole and betamethasone dipropionate cream is for use on skin only. Do not use clotrimazole and betamethasone dipropionate cream in your eyes, mouth, or vagina.

What is clotrimazole and betamethasone dipropionate cream?

Before using clotrimazole and betamethasone dipropionate cream, tell your healthcare provider about all your medical conditions, including if you:

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take other corticosteroid medicines by mouth or use other products on your skin or scalp that contain corticosteroids.

What should I avoid while using clotrimazole and betamethasone dipropionate cream?

Clotrimazole and betamethasone dipropionate cream should not be used to treat diaper rash or redness. You should avoid applying clotrimazole and betamethasone dipropionate cream in the diaper area.

How should I use clotrimazole and betamethasone dipropionate cream?

What are the possible side effects of clotrimazole and betamethasone dipropionate cream?

Clotrimazole and betamethasone dipropionate cream may cause serious side effects, including:

The most common side effects of clotrimazole and betamethasone dipropionate cream include burning, tingling, rash, swelling, and infections.

These are not all the possible side effects of clotrimazole and betamethasone dipropionate cream.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store clotrimazole and betamethasone dipropionate cream?

General information about the safe and effective use of clotrimazole and betamethasone dipropionate cream.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about clotrimazole and betamethasone dipropionate cream that is written for health professionals. Do not use clotrimazole and betamethasone dipropionate cream for a condition for which it was not prescribed. Do not give clotrimazole and betamethasone dipropionate cream to other people, even if they have the same symptoms that you have. It may harm them.

What are the ingredients in clotrimazole and betamethasone dipropionate cream?

Active ingredients: clotrimazole and betamethasone dipropionate

Inactive ingredients: benzyl alcohol as a preservative, ceteareth-30, cetyl alcohol plus stearyl alcohol, mineral oil, phosphoric acid, propylene glycol, purified water, sodium phosphate monobasic monohydrate, and white petrolatum

Manufactured for:
Prasco Laboratories
Mason, OH 45040, USA

Manufactured by:
Schering Plough Canada Inc., Pointe Claire, Quebec H9R 1B4, Canada

Revised: June 2014

usppi-gmk5335A-cr-1406r001

PRINCIPAL DISPLAY PANEL - 45 g Tube Carton

NDC 66993-898-45

PRASCO

Clotrimazole and
Betamethasone
Dipropionate
Cream

FOR TOPICAL USE ONLY;
NOT FOR OPHTHALMIC,
ORAL, OR INTRAVAGINAL
USE; NOT RECOMMENDED
FOR PATIENTS UNDER
THE AGE OF 17 YEARS
AND NOT RECOMMENDED
FOR DIAPER DERMATITIS.

Rx only

45 g

Principal Display Panel - 45 g Tube Carton
CLOTRIMAZOLE AND BETAMETHASONE DIPROPIONATE 
clotrimazole and betamethasone dipropionate cream
Product Information
Product TypeHUMAN PRESCRIPTION DRUG LABELItem Code (Source)NDC:66993-898
Route of AdministrationTOPICALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
CLOTRIMAZOLE (CLOTRIMAZOLE) CLOTRIMAZOLE10 mg  in 1 g
BETAMETHASONE DIPROPIONATE (BETAMETHASONE) BETAMETHASONE0.5 mg  in 1 g
Inactive Ingredients
Ingredient NameStrength
WATER 
MINERAL OIL 
PETROLATUM 
CETYL ALCOHOL 
STEARYL ALCOHOL 
CETEARETH-30 
PROPYLENE GLYCOL 
SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE 
PHOSPHORIC ACID 
BENZYL ALCOHOL 
SODIUM HYDROXIDE 
Product Characteristics
ColorWHITE (white to off-white) Score    
ShapeSize
FlavorImprint Code
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:66993-898-151 in 1 BOX
115 g in 1 TUBE
2NDC:66993-898-451 in 1 BOX
245 g in 1 TUBE
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA01882707/10/1984
Labeler - Prasco Laboratories (065969375)
Registrant - Merck Sharp & Dohme Corp. (001317601)
Establishment
NameAddressID/FEIBusiness Operations
Schering Plough Canada Inc.207093332MANUFACTURE(66993-898)
Establishment
NameAddressID/FEIBusiness Operations
MSD International GmbH (Singapore Branch)595320830API MANUFACTURE(66993-898)
Establishment
NameAddressID/FEIBusiness Operations
Bayer Hispania, S.L.462205374API MANUFACTURE(66993-898)

Revised: 6/2014
Document Id: b55e700d-ae7b-4347-99f9-96e37b170d8a
Set id: f4e9d5a1-cc99-4907-bc62-a636fc0dcab5
Version: 2
Effective Time: 20140630
 
Prasco Laboratories