LOTRISONE Cream Ref.[10590] Active ingredients: Betamethasone Clotrimazole

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.

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.

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.

Risk Summary

There are no available data on topical betamethasone dipropionate or clotrimazole use in pregnant women to identify a LOTRISONE cream associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Observational studies suggest an increased risk of low birthweight infants with the use of potent or very potent topical corticosteroid during 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.

There have been no reproduction studies performed in animals or humans with the combination of clotrimazole and betamethasone dipropionate. In an animal reproduction study, betamethasone dipropionate caused malformations (i.e., umbilical hernias, cephalocele, and cleft palate) in pregnant rabbits when given by the intramuscular route during organogenesis [see Data]. The available data do not allow the calculation of relevant comparisons between the systemic exposure of clotrimazole and/or betamethasone dipropionate observed in the animal studies to the systemic exposure that would be expected in humans after topical use of LOTRISONE cream.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

Clotrimazole:

Studies in pregnant rats treated during organogenesis with intravaginal doses up to 100 mg/kg/day 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 was maternally lethal, and therefore, fetuses were not evaluated in this group. Also in this study, doses up to 50 mg/kg/day had no adverse effects on dams or fetuses. However, in the combined fertility, embryofetal development, and postnatal development study conducted in rats, 50 mg/kg/day clotrimazole was associated with reduced maternal weight gain and reduced numbers of offspring reared to 4 weeks [see Nonclinical Toxicology (13.1)].

Oral clotrimazole doses of 25, 50, 100, and 200 mg/kg/day did not cause malformations in pregnant mice. No evidence of maternal toxicity or embryotoxicity was seen in pregnant rabbits dosed orally during organogenesis with 60, 120, or 180 mg/kg/day.

Betamethasone Dipropionate:

Betamethasone dipropionate caused malformations when given to pregnant rabbits during organogenesis by the intramuscular route at doses of 0.05 mg/kg/day. The abnormalities observed included umbilical hernias, cephalocele, and cleft palates.

Risk Summary

There are no data regarding the excretion of betamethasone dipropionate or clotrimazole into breast milk, the effects on the breastfed infant, or the effects on milk production after topical application to women who are breastfeeding.

It is possible that topical administration of betamethasone dipropionate could result in sufficient systemic absorption to produce detectable quantities in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LOTRISONE cream and any potential adverse effects on the breastfed infant from LOTRISONE cream or from the underlying maternal condition.

Clinical Considerations

To minimize potential exposure to the breastfed infant via breast milk, 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 (8.4)].

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.

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.