5.1 Effects on Endocrine System

LOTRISONE 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, LOTRISONE 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 LOTRISONE 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 LOTRISONE cream in the treatment of diaper dermatitis is not recommended.

5.3 Ophthalmic Adverse Reactions

Use of topical corticosteroids may increase the risk of posterior subcapsular cataracts and glaucoma. Cataracts and glaucoma have been reported in postmarketing experience with the use of topical corticosteroid products, including topical betamethasone products [see Adverse Reactions (6.2)].

Avoid contact of LOTRISONE cream with eyes. Advise patients to report any visual symptoms and consider referral to an ophthalmologist for evaluation.

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 LOTRISONE 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).

Ophthalmic adverse reactions of blurred vision, cataracts, glaucoma, increased intraocular pressure, and central serous chorioretinopathy have been reported with the use of topical corticosteroids, including topical betamethasone products.

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

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The use of LOTRISONE 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 LOTRISONE cream. In open-label trials, 17 of 43 (39.5%) evaluable pediatric subjects (aged 12-16 years old) using LOTRISONE 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 LOTRISONE 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 LOTRISONE cream in the treatment of diaper dermatitis.

8.5 Geriatric Use

Clinical studies of LOTRISONE 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 LOTRISONE cream under occlusion, such as in diaper dermatitis, is not recommended.

Postmarket adverse event reporting for LOTRISONE 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.

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

12.3 Pharmacokinetics

Skin penetration and systemic absorption of clotrimazole and betamethasone dipropionate following topical application of LOTRISONE 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

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of the combination of clotrimazole and betamethasone dipropionate or either component individually.

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.

In a combined study of the effects of clotrimazole on fertility, embryofetal development, and postnatal development, male and female rats were dosed orally (diet admixture) with dose levels of 5, 10, 25, or 50 mg/kg/day 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.

Reproductive studies with betamethasone dipropionate conducted in rabbits at doses of 1.0 mg/kg/day by the intramuscular route and in mice up to 33 mg/kg/day by the intramuscular route indicated no impairment of fertility except for dose-related increases in fetal resorption rates in both species.

LOTRISONE cream is white to off-white and supplied in 15-gram (NDC 0085-0924-01) and 45-gram tubes (NDC 0085-0924-02), 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

Pregnancy

Advise pregnant women that LOTRISONE cream may increase the risk of having a low birthweight infant and to use LOTRISONE cream on the smallest area of skin and for the shortest duration possible [see Use in Specific Populations (8.1)].

Lactation

Advise a woman to use LOTRISONE cream on the smallest area of skin and for the shortest duration possible while breastfeeding. Advise breastfeeding women not to apply LOTRISONE cream directly to the nipple and areola to avoid direct infant exposure [see Use in Specific Populations (8.2)].

Important Administration Instructions

Inform patients of the following:

• Use LOTRISONE cream as directed by the physician. It is for external use only.
• Avoid contact with the eyes, the mouth, or intravaginally.
• Advise patients to report any visual symptoms to their healthcare providers.
• Do not use LOTRISONE cream on the face or underarms.
• Do not use more than 45 grams of LOTRISONE cream per week.
• When using LOTRISONE cream in the groin area, patients should use the medication for 2 weeks only, and apply the cream sparingly. Patients should wear loose-fitting clothing. Notify the physician if the condition persists after 2 weeks.
• Do not use LOTRISONE cream for any disorder other than that for which it was prescribed.
• Do not bandage, cover or wrap the treatment area unless directed by the physician. Avoid use of LOTRISONE cream in the diaper area, as diapers or plastic pants may constitute occlusive dressing.
• Report any signs of local adverse reactions to the physician. Advise patients that local reactions and skin atrophy are more likely to occur with occlusive use or prolonged use.
• This medication is to be used for the full prescribed treatment time, even though the symptoms may have improved. Notify the physician if there is no improvement after 1 week of treatment for tinea cruris or tinea corporis, or after 2 weeks for tinea pedis.