Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of Cushing's syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment.
Conditions which augment systemic absorption include use over large surface areas, prolonged use, and use under occlusive dressings. Use of more than one corticosteroid-containing product at the same time may increase total systemic glucocorticoid exposure. Patients applying LOTRISONE® Cream or Lotion to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA axis suppression. This may be done by using the ACTH stimulation, morning plasma cortisol, and urinary-free cortisol tests.
If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent corticosteroid. Recovery of HPA axis function is generally prompt upon discontinuation of topical corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur, requiring supplemental systemic corticosteroids.
In a small study, 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 eight normal subjects on whom LOTRISONE Cream was applied exhibited low morning plasma cortisol levels during treatment. One of these subjects had an abnormal Cortrosyn test. The effect on morning plasma cortisol was transient and subjects recovered 1 week after discontinuing dosing. In addition, two separate studies in pediatric patients demonstrated adrenal suppression as determined by cosyntropin testing (see PRECAUTIONS, Pediatric Use section).
Pediatric patients may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios (see PRECAUTIONS, Pediatric Use section).
If irritation develops, LOTRISONE Cream or Lotion should be discontinued and appropriate therapy instituted.
THE SAFETY OF LOTRISONE CREAM OR LOTION HAS NOT BEEN DEMONSTRATED IN THE TREATMENT OF DIAPER DERMATITIS. ADVERSE EVENTS CONSISTENT WITH CORTICOSTEROID USE HAVE BEEN OBSERVED IN PATIENTS TREATED WITH LOTRISONE CREAM FOR DIAPER DERMATITIS. THE USE OF LOTRISONE CREAM OR LOTION IN THE TREATMENT OF DIAPER DERMATITIS IS NOT RECOMMENDED.
Information for Patients
Patients using LOTRISONE Cream or Lotion should receive the following information and instructions:
- The medication is to be used as directed by the physician and is not recommended for use longer than the prescribed time period. It is for external use only. Avoid contact with the eyes, the mouth, or intravaginally.
- 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.
- This medication should only be used for the disorder for which it was prescribed.
- Other corticosteroid-containing products should not be used with LOTRISONE without first talking with your physician.
- The treated skin area should not be bandaged, covered, or wrapped so as to be occluded (see DOSAGE AND ADMINISTRATION).
- Any signs of local adverse reactions should be reported to your physician.
- Patients should avoid sources of infection or reinfection.
- When using LOTRISONE Cream or Lotion in the groin area, patients should use the medication for 2 weeks only, and apply the cream or lotion sparingly. Patients should wear loose-fitting clothing. Notify the physician if the condition persists after 2 weeks.
- The safety of LOTRISONE Cream or Lotion has not been demonstrated in the treatment of diaper dermatitis. Adverse events consistent with corticosteroid use have been observed in patients treated with LOTRISONE Cream for diaper dermatitis. The use of LOTRISONE Cream or Lotion in the treatment of diaper dermatitis is not recommended.
If there is a lack of response to LOTRISONE Cream or Lotion, appropriate confirmation of the diagnosis, including possible mycological studies, is indicated before instituting another course of therapy.
The following tests may be helpful in evaluating HPA axis suppression due to the corticosteroid components:
- Urinary-free cortisol test
- Morning plasma cortisol test
- ACTH (cosyntropin) stimulation test
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. This pattern of response is similar to that of dexamethasone and hydrocortisone.
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 18 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.
Teratogenic Effects: Pregnancy Category C
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 (215 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 (1855 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.
There are no adequate and well-controlled studies in pregnant women of the teratogenic effects of topically applied corticosteroids. Therefore, LOTRISONE Cream or Lotion should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could 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 LOTRISONE Cream or Lotion is administered to a nursing woman.
Adverse events consistent with corticosteroid use have been observed in patients under 12 years of age treated with LOTRISONE Cream. In open-label studies, 17 of 43 (39.5%) evaluable pediatric patients (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 study, 8 of 17 (47.1%) evaluable pediatric patients (aged 12 16 years old) using LOTRISONE Cream for treatment of tinea cruris demonstrated adrenal suppression as determined by cosyntropin testing. THE USE OF LOTRISONE CREAM OR LOTION IN THE TREATMENT OF PATIENTS UNDER 17 YEARS OF AGE OR PATIENTS WITH DIAPER DERMATITIS IS NOT RECOMMENDED.
Because of higher ratio of skin surface area to body mass, pediatric patients under the age of 12 years are at a higher risk with LOTRISONE Cream or Lotion. The studies described above suggest that pediatric patients under the age of 17 years may also have this risk. They are at increased risk of developing Cushing's syndrome while on treatment and adrenal insufficiency after withdrawal of treatment. Adverse effects, including striae and growth retardation, have been reported with inappropriate use of LOTRISONE Cream in infants and children (see PRECAUTIONS and ADVERSE REACTIONS).
Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing's syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include low plasma cortisol levels and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.
Clinical studies of LOTRISONE Cream and Lotion did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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. THE USE OF LOTRISONE CREAM OR LOTION UNDER OCCLUSION, SUCH AS IN DIAPER DERMATITIS, IS NOT RECOMMENDED.