CLOBETASOL PROPIONATE
DESCRIPTION:
CLOBETOL (clobetasol propionate cream and ointment) Cream and Ointment contain
the active compound clobetasol propionate, a synthetic corticosteroid, for
topical dermatologic use. Clobetasol, an analog of prednisolone, has a high
degree of glucocorticoid activity and a slight degree of mineralocorticoid
activity.
Chemically, clobetasol propionate is (11beta,16beta)-21-chloro-9-fluoro-11-
hydroxy- 16-methyl-17-(1-oxopropoxy)-pregna-1,4-diene- 3,20-dione.
Clobetasol propionate has the empirical formula C25H32ClFO5 and a molecular
weight of 467. It is a white to cream-colored crystalline powder insoluble in
water.
CLOBETOL Cream contains clobetasol propionate 0.5mg/g in a cream base of
propylene glycol, glyceryl monostearate, cetostearyl alcohol, glyceryl stearate,
PEG 100 stearate, white wax, chlorocresol, sodium citrate, citric acid
monohydrate, and purified water.
CLOBETOL Ointment contains clobetasol propionate 0.5 mg/g in a base of propylene
glycol, sorbitan sesquioleate, and white petrolatum.
ACTIONS/CLINICAL PHARMACOLOGY:
Like other topical corticosteroids, clobetasol propionate has anti-inflammatory,
antipruritic, and vasoconstrictive properties. The mechanism of the anti-
inflammatory activity of the topical steroids, in general, is unclear. However,
corticosteroids are thought to act by the induction of phospholipase A2
inhibitory proteins, collectively called lipocortins. It is postulated that
these proteins control the biosynthesis of potent mediators of inflammation such
as prostaglandins and leukotrienes by inhibiting the release of their common
precursor, arachidonic acid. Arachidonic acid is released from membrane
phospholipids by phospholipase A2.
PHARMACOKINETICS: The extent of percutaneous absorption of topical
corticosteroids is determined by many factors, including the vehicle and the
integrity of the epidermal barrier. Occlusive dressing with hydrocortisone for
up to 24 hours has not been demonstrated to increase penetration; however,
occlusion of hydrocortisone for 96 hours markedly enhances penetration. Topical
corticosteroids can be absorbed from normal intact skin. Inflammation and/or
other disease processes in the skin may increase percutaneous absorption.
Studies performed with CLOBETOL Cream and Ointment indicate that they are in the
super-high range of potency as compared with other topical corticosteroids.
INDICATIONS AND USAGE:
CLOBETOL Cream and Ointment are super-high potency corticosteroid formulations
indicated for the relief of the inflammatory and pruritic manifestations of
corticosteroid-responsive dermatoses. Treatment beyond 2 consecutive weeks is
not recommended, and the total dosage should not exceed 50 g/week because of the
potential for the drug to suppress the hypothalamic-pituitary- adrenal (HPA)
axis. Use in children under 12 years of age is not recommended.
As with other highly active corticosteroids, therapy should be discontinued when
control has been achieved. If no improvement is seen within 2 weeks,
reassessment of the diagnosis may be necessary.
CONTRAINDICATIONS:
CLOBETOL Cream and Ointment are contraindicated in those patients with a history
of hypersensitivity to any of the components of the preparations.
PRECAUTIONS:
GENERAL: CLOBETOL Cream and Ointment should not be used in the treatment of
rosacea or perioral dermatitis, and should not be used on the face, groin, or
axillae.
Systemic absorption of topical corticosteroids can produce reversible HPA axis
suppression with the potential for glucocorticosteroid insufficiency after
withdrawal from treatment. Manifestations of Cushing's syndrome, hyperglycemia,
and glucosuria can also be produced in some patients by systemic absorption of
topical corticosteroids while on therapy.
Patients applying a topical steroid 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, A.M. plasma cortisol, and
urinary free cortisol tests. Patients receiving super-potent corticosteroids
should not be treated for more than 2 weeks at a time, and only small areas
should be treated at any one time due to the increased risk of HPA suppression.
CLOBETOL Cream and Ointment produced HPA axis suppression when used at doses as
low as 2g/day for 1 week in patients with eczema.
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. For information on systemic supplementation, see prescribing
information for those products.
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).
If irritation develops, CLOBETOL Cream and Ointment should be discontinued and
appropriate therapy instituted. Allergic contact dermatitis with corticosteroids
is usually diagnosed by observing Failure To Heal rather than noting a clinical
exacerbation as with most topical products not containing corticosteroids. Such
an observation should be corroborated with appropriate diagnostic patch testing.
If concomitant skin infections are present or develop, an appropriate antifungal
or antibacterial agent should be used. If a favorable response does not occur
promptly, use of CLOBETOL Cream and Ointment should be discontinued until the
infection has been adequately controlled.
INFORMATION FOR PATIENTS: Patients using topical corticosteroids should receive
the following information and instructions:
1. This medication is to be used as directed by the physician. It is for
external use only. Avoid contact with the eyes.
2. This medication should not be used for any disorder other than that for which
it was prescribed.
3. The treated skin area should not be bandaged, otherwise covered, or wrapped
so as to be occlusive unless directed by the physician.
4. Patients should report any signs of local adverse reactions to the physician.
LABORATORY TESTS: The following tests may be helpful in evaluating patients for
HPA axis suppression:
ACTH stimulation test
A.M. plasma cortisol test
Urinary free cortisol test
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: Long-term animal studies
have not been performed to evaluate the carcinogenic potential of clobetasol
propionate.
Studies in the rat following oral administration at dosage levels up to 50 mg/kg
per day revealed that the females exhibited an increase in the number of
resorbed embryos and a decrease in the number of living fetuses at the highest
dose.
Clobetasol propionate was nonmutagenic in three different test systems: the Ames
test, the Saccharomyces Cerevisiae gene conversion assay, and the E. Coli B WP2
fluctuation test.
PREGNANCY: TERATOGENIC EFFECTS: PREGNANCY CATEGORY C: Corticosteroids have been
shown to be teratogenic in laboratory animals when administered systemically at
relatively low dosage levels. Some corticosteroids have been shown to be
teratogenic after dermal application to the laboratory animals.
Clobetasol propionate has not been tested for teratogenicity when applied
topically; however, it is absorbed percutaneously, and when administered
subcutaneously it was a significant teratogen in both the rabbit and mouse.
Clobetasol propionate has greater teratogenic potential than steroids that are
less potent.
Teratogenicity studies in mice using the subcutaneous route resulted in
fetotoxicity at the highest dose tested (1 mg/kg) and teratogenicity at all dose
levels tested down to 0.03 mcg/kg. These doses are approximately 0.33 and 0.01
times, respectively, the human topical dose of CLOBETOL Cream and Ointment.
Abnormalities seen included cleft palate and skeletal abnormalities.
In rabbits, clobetasol propionate was teratogenic at doses of 3 and 10 mcg/kg.
These doses are approximately 0.001 and 0.003 times, respectively, the human
topical dose of CLOBETOL Cream and Ointment. Abnormalities seen included cleft
palate, cranioschisis, and other skeletal abnormalities.
There are no adequate and well controlled studies of the teratogenic potential
of clobetasol propionate in pregnant women. CLOBETOL Cream and Ointment should
be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus.
NURSING MOTHERS: 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 CLOBETOL Cream or Ointment is
administered to a nursing woman.
PEDIATRIC USE: Safety and effectiveness of CLOBETOL in pediatric patients have
not been established. Use in children under 12 years of age is not recommended.
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 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 effects including striae have been reported with inappropriate use of
topical corticosteroids in infants and children.
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.
ADVERSE REACTIONS:
In controlled clinical trials, the most frequent adverse reactions reported for
CLOBETOL Cream were burning and stinging sensation in 1% of treated patients.
Less frequent adverse reactions were itching, skin atrophy, and cracking and
fissuring of the skin.
In controlled clinical trials, the most frequent adverse events reported for
CLOBETOL Ointment were burning sensation, irritation, and itching in 0.5% of
treated patients. Less frequent adverse reactions were stinging, cracking,
erythema, folliculitis, numbness of fingers, skin atrophy, and telangiectasia.
Cushing's syndrome has been reported in infants and adults as a result of
prolonged use of topical clobetasol propionate formulations
The following additional local adverse reactions have been reported with topical
corticosteroids, and they may occur more frequently with the use of occlusive
dressings and higher potency corticosteroids. These reactions are listed in an
approximately decreasing order of occurrence: dryness, acneiform eruptions,
hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary
infection, irritation, striae, and miliaria.
OVERDOSAGE:
Topically applied CLOBETOL Cream and Ointment can be absorbed in sufficient
amounts to produce systemic effects (see PRECAUTIONS).
DOSAGE AND ADMINISTRATION:
Apply a thin layer of CLOBETOL Cream or Ointment to the affected skin areas
twice daily and rub in gently and completely.
CLOBETOL Cream and Ointment are super-high potency topical corticosteroids;
therefore, TREATMENT SHOULD BE LIMITED TO 2 CONSECUTIVE WEEKS, AND AMOUNTS
GREATER THAN 50G/WEEK SHOULD NOT BE USED.
As with other highly active corticosteroids, therapy should be discontinued when
control has been achieved. If no improvement is seen within 2 weeks,
reassessment of diagnosis may be necessary.
CLOBETOL Cream and Ointment should not be used with occlusive dressings.
************************************************************************