Included as part of the PRECAUTIONS section.
Effects On Endocrine System
ULTRAVATE lotion is a topical corticosteroid that has
been shown to suppress the hypothalamic-pituitary-adrenal (HPA) axis.
Systemic effects of topical corticosteroids may include
reversible HPA axis suppression, with the potential for glucocorticosteroid
insufficiency. This may occur during treatment or upon withdrawal of treatment
of the topical corticosteroid.
The potential for hypothalamic-pituitary adrenal (HPA)
suppression with ULTRAVATE lotion was evaluated in a study of 20 adult subjects
with moderate to severe plaque psoriasis involving ≥ 20% of their body
surface area. ULTRAVATE lotion produced HPA axis suppression when used twice
daily for two weeks in 5 out of 20 (25%) adult patients with plaque psoriasis.
Recovery of HPA axis function was generally prompt with the discontinuation of
treatment [see CLINICAL PHARMACOLOGY].
Because of the potential for systemic absorption, use of
topical corticosteroids, including ULTRAVATE lotion, may require that patients
be evaluated periodically for evidence of HPA axis suppression. Factors that
predispose a patient using a topical corticosteroid to HPA axis suppression
include the use of more potent corticosteroids, use over large surface areas,
prolonged use, occlusive use, use on an altered skin barrier, concomitant use
of multiple corticosteroid-containing products, liver failure, and young age.
An ACTH stimulation test may be helpful in evaluating patients for HPA axis
If HPA axis suppression is documented, attempt to
gradually withdraw the drug, reduce the frequency of application, or substitute
a less potent steroid. Manifestations of adrenal insufficiency may require supplemental
systemic corticosteroids. Recovery of HPA axis function is generally prompt and
complete upon discontinuation of topical corticosteroids.
Systemic effects of topical corticosteroids may also
include Cushing's syndrome, hyperglycemia, and glucosuria. Use of more than one
corticosteroid-containing product at the same time may increase the total
systemic exposure to topical corticosteroids.
Pediatric patients may be more susceptible than adults to
systemic toxicity from the use of topical corticosteroids due to their larger
surface-to-body mass ratios [see Use in Specific Populations].
Local Adverse Reactions
Local adverse reactions from topical corticosteroids may
include atrophy, striae, telangiectasias, burning, itching, irritation,
dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral
dermatitis, allergic contact dermatitis, secondary infection, and miliaria.
These may be more likely to occur with occlusive use, prolonged use, or use of
higher potency corticosteroids, including ULTRAVATE lotion. Some local adverse
reactions may be irreversible.
Concomitant Skin Infections
Use an appropriate antimicrobial agent if a skin
infection is present or develops. If a favorable response does not occur
promptly, discontinue use of ULTRAVATE lotion until the infection has been
Allergic Contact Dermatitis
Allergic contact dermatitis with corticosteroids is
usually diagnosed by observing failure to heal rather than noting a clinical
exacerbation. Consider confirmation of a clinical diagnosis of allergic contact
dermatitis by appropriate patch testing. Discontinue ULTRAVATE lotion if
allergic contact dermatitis is established.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term animal studies have not been performed to
evaluate the carcinogenic potential of halobetasol propionate.
In a 90-day repeat-dose toxicity study in rats, topical
administration of halobetasol propionate lotion at dose concentrations from
0.05% to 0.1% or from 0.25 to 0.5 mg/kg/day of halobetasol propionate resulted
in a toxicity profile consistent with long-term exposure to corticosteroids
including adrenal atrophy, histopathological changes in several organ systems
indicative of severe immune suppression, and opportunistic fungal and bacterial
infections. A no observable adverse effect level (NOAEL) could not be
determined in this study. Although the clinical relevance of the findings in
animals to humans is not clear, sustained glucocorticoid-related immune
suppression may increase the risk of infection and possibly the risk of
Halobetasol propionate was not found to be genotoxic in
the Ames/Salmonella assay, in the Chinese hamster CHO/HGPRT assay, in the mouse
micronucleus test, in the sister chromatid exchange test in somatic cells of
the Chinese hamster, or in the chromosome aberration test in somatic cells of
Chinese hamsters. Positive mutagenicity effects were observed in two
genotoxicity assays: Chinese hamster nuclear anomaly test and mouse lymphoma
gene mutation assay in vitro.
Studies in the rat following oral administration at dose
levels up to 50 μg/kg/day indicated no impairment of fertility or general
Use In Specific Populations
There are no data on topical halobetasol propionate use
in pregnant women to inform any drug-associated risks for birth defects or
miscarriage. In animal reproduction studies, halobetasol propionate
administered systemically during organogenesis to pregnant rats at 13 and 33
times the human topical dose and to pregnant rabbits at 3 times the human
topical dose resulted in teratogenic and embryotoxic effects [see Data].
The clinical relevance of the animal findings is not clear.
The background risk of major birth defects and
miscarriage for the indicated population are unknown. In the U.S. general
population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
Halobetasol propionate has been shown to be teratogenic
in rats and rabbits when given systemically during organogenesis at doses of
0.04 to 0.1 mg/kg/day in rats and 0.01 mg/kg/day in rabbits. These doses are
approximately 13, 33, and 3 times, respectively, the human topical dose of
halobetasol propionate, 0.05%. Halobetasol propionate was embryotoxic in rabbits
but not in rats.
Cleft palate was observed in both rats and rabbits.
Omphalocele was seen in rats, but not in rabbits.
There are no data on the presence of halobetasol
propionate or its metabolites in human milk,, the effects on the breastfed
infant, or the effects on milk production after topical application to women
who are breastfeeding.
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. The developmental and health benefits of
breastfeeding should be considered along with the mother's clinical need for
ULTRAVATE lotion and any potential adverse effects on the breastfed infant from
ULTRAVATE lotion or from the underlying maternal condition.
Advise breastfeeding women not to apply ULTRAVATE lotion
directly to the nipple and areola to avoid direct infant exposure.
Safety and effectiveness of ULTRAVATE lotion in patients
younger than 18 years of age have not been established.
Because of higher skin surface area to body mass ratios,
pediatric patients are at a greater risk than adults of HPA axis suppression
and Cushing's syndrome when they are treated with topical corticosteroids. They
are therefore also at greater risk of adrenal insufficiency during or after
withdrawal of treatment. Adverse reactions including striae have been reported
with use of topical corticosteroids in infants and children [see WARNINGS
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 an
absence of response to ACTH stimulation. Manifestations of intracranial
hypertension include bulging fontanelles, headaches, and bilateral papilledema
[see WARNINGS AND PRECAUTIONS].
Clinical studies with ULTRAVATE lotion included 89
subjects aged 65 years and over. No overall differences in safety or
effectiveness were observed between these patients and those younger than 65
years. Clinical studies of ULTRAVATE lotion did not include sufficient numbers
of subjects aged 65 and over to determine whether they respond differently from