DESCRIPTION:
DIPROVATE Ointment contains betamethasone dipropionate, USP, a synthetic
adrenocorticosteroid, for dermatologic use. Betamethasone, an analog of
prednisolone, has a high degree of corticosteroid activity and a slight degree
of mineralocorticoid activity. Betamethasone dipropionate is the 17,21-
dipropionate ester of betamethasone.
Chemically, betamethasone dipropionate is 9-fluoro-11beta, 17,21-trihydroxy-
16beta-methyl- pregna-1,4-diene-3,20-dione 17, 21-dipropionate, with the
empirical formula C28 H37 FO7, a molecular weight of 504.6
Betamethasone dipropionate is a white to creamy white, odorless crystalline
powder, insoluble in water.
Each gram of DIPROVATE Ointment 0.05% contains: 0.64 mg betamethasone
dipropionate, USP (equivalent to 0.5 mg betamethasone), in ACTIBASE(R), an
optimized vehicle of propylene glycol, propylene glycol stearate, white wax, and
white petrolatum.
ACTIONS/CLINICAL PHARMACOLOGY:
The corticosteroids are a class of compounds comprising steroid hormones
secreted by the adrenal cortex and their synthetic analogs. In pharmacologic
doses, corticosteroids are used primarily for their anti-inflammatory and/or
immunosuppressive effects.
Topical corticosteroids, such as betamethasone dipropionate, are effective in
the treatment of corticosteroid-responsive dermatoses primarily because of their
anti-inflammatory, anti- pruritic, and vasoconstrictive actions. However, while
the physiologic, pharmacologic, and clinical effects of the corticosteroids are
well known, the exact mechanisms of their actions in each disease are uncertain.
Betamethasone dipropionate, a corticosteroid, has been shown to have topical
(dermatologic) and systemic pharmacologic and metabolic effects characteristic
of this class of drugs.
PHARMACOKINETICS 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. (See
DOSAGE AND ADMINISTRATION section.)
Topical corticosteroids can be absorbed from normal intact skin. Inflammation
and/or other disease processes in the skin may increase percutaneous absorption.
Occlusive dressings substantially increase the percutaneous absorption of
topical corticosteroids. (See DOSAGE AND ADMINISTRATION section.)
Once absorbed through the skin, topical corticosteroids enter pharmacokinetic
pathways 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.
At 14 g per day, DIPROVATE Ointment was shown to depress the plasma levels of
adrenal cortical hormones following repeated application to diseased skin in
patients with psoriasis. Adrenal depression in these patients was transient, and
rapidly returned to normal upon cessation of treatment. At 7 g per day (3.5 g
bid), DIPROVATE Ointment was shown to cause minimal inhibition of the
hypothalamic-pituitary-adrenal (HPA) axis when applied two times daily for 2 to
3 weeks, in normal patients and in patients with psoriasis and eczematous
disorders.
With 6 to 7 g of DIPROVATE Ointment applied once daily for 3 weeks, no
significant inhibition of the HPA axis was observed in patients with psoriasis
and atopic dermatitis, as measured by plasma cortisol and 24-hour urinary 17-
hydroxycorticosteroid levels.
INDICATIONS AND USAGE:
DIPROVATE Ointment is indicated for relief of the inflammatory and pruritic
manifestations of corticosteroid-responsive dermatoses.
CONTRAINDICATIONS:
DIPROVATE Ointment is contraindicated in patients who are hypersensitive to
betamethasone dipropionate, to other corticosteroids, or to any ingredient in
this preparation.
PRECAUTIONS:
GENERAL Systemic absorption of topical corticosteroids has produced reversible
HPA axis suppression, manifestations of Cushing's syndrome, hyperglycemia, and
glucosuria in some patients.
Conditions which augment systemic absorption include the application of the more
potent corticosteroids, use over large surface areas, prolonged use, and the
addition of occlusive dressings. (See DOSAGE AND ADMINISTRATION section.)
Therefore, patients receiving a large dose of a potent topical steroid applied
to a large surface area should be evaluated periodically for evidence of HPA
axis suppression by using the urinary free cortisol and ACTH stimulation 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
steroid.
Recovery of HPA axis function is generally prompt and complete upon
discontinuation of the drug. Infrequently, signs and symptoms of steroid
withdrawal may occur, requiring supplemental systemic corticosteroids.
Children may absorb proportionally larger amounts of topical corticosteroids and
thus be more susceptible to systemic toxicity. (See PRECAUTIONS-PEDIATRIC USE.)
If irritation develops, topical corticosteroids should be discontinued and
appropriate therapy instituted.
In the presence of dermatological infections, the use of an appropriate
antifungal or antibacterial agent should be instituted. If a favorable response
does not occur promptly, the corticosteroid 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 and should not be
used longer than the prescribed time period. It is for external use only.
Avoid contact with the eyes.
2. Patients should be advised not to use this medication for any disorder other
than that for which it was prescribed.
3. The treated skin area should not be bandaged or otherwise covered or wrapped
as to be occlusive. (See DOSAGE AND ADMINISTRATION section.)
4. Patients should report any signs of local adverse reactions.
LABORATORY TESTS The following tests may be helpful in evaluating HPA axis
suppression:
Urinary free cortisol test
ACTH stimulation test
CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY Long-term animal
studies have not been performed to evaluate the carcinogenic potential or the
effect on fertility of topically applied corticosteroids.
Studies to determine mutagenicity with prednisolone have revealed negative
results.
PREGNANCY CATEGORY C Corticosteroids are generally teratogenic in laboratory
animals when administered systemically at relatively low dosage levels. The more
potent corticosteroids have been shown to be teratogenic after dermal
application in laboratory animals. There are no adequate and well-controlled
studies of the teratogenic effects of topically applied corticosteroids in
pregnant women. Therefore, topical corticosteroids should be used during
pregnancy only if the potential benefit justifies the potential risk to the
fetus. Drugs of this class should not be used extensively on pregnant patients,
in large amounts, or for prolonged periods of time.
NURSING MOTHERS It is not known whether topical administration of
corticosteroids could result in sufficient systemic absorption to produce
detectable quantities in breast milk. Systemically administered corticosteroids
are secreted into breast milk in quantities not likely to have a deleterious
effect on the infant. Nevertheless, caution should be exercised when topical
corticosteroids are prescribed for a nursing woman.
PEDIATRIC USE Use of DIPROVATE Ointment in children under 12 years is not
recommended.
PEDIATRIC PATIENTS MAY DEMONSTRATE GREATER SUSCEPTIBILITY TO TOPICAL
CORTICOSTEROID-INDUCED HPA AXIS SUPPRESSION AND CUSHING'S SYNDROME THAN MATURE
PATIENTS BECAUSE OF A LARGER SKIN SURFACE AREA TO BODY WEIGHT RATIO.
Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing's syndrome, and
intracranial hypertension have been reported in children receiving topical
corticosteroids. Manifestations of adrenal suppression in children include
linear growth retardation, delayed weight gain, low plasma cortisol levels, and
absence of response to ACTH stimulation. Manifestations of intracranial
hypertension include bulging fontanelles, headaches, and bilateral papilledema.
Administration of topical corticosteroids to children should be limited to the
least amount compatible with an effective therapeutic regimen. Chronic
corticosteroid therapy may interfere with the growth and development of
children.
ADVERSE REACTIONS:
The local adverse reactions were reported with DIPROVATE Ointment applied either
once or twice a day during clinical studies are as follows: erythema, 3 per 767
patients; folliculitis, 2 per 767 patients; pruritus, 2 per 767 patients;
vesiculation, 1 per 767 patients.
The following local adverse reactions are reported infrequently when topical
corticosteroids are used as recommended. These reactions are listed in an
approximate decreasing order of occurrence: burning, itching, irritation,
dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation,
perioral dermatitis, allergic contact dermatitis, maceration of the skin,
secondary infection, skin atrophy, striae, miliaria.
Systemic absorption of topical corticosteroids has produced reversible HPA axis
suppression, manifestations of Cushing's syndrome, hyperglycemia, and glucosuria
in some patients.
OVERDOSAGE:
Topically applied corticosteroids can be absorbed in sufficient amounts to
produce systemic effects. (See PRECAUTIONS.)
DOSAGE AND ADMINISTRATION:
Apply a thin film of DIPROVATE Ointment to the affected skin areas once or twice
daily. Treatment with DIPROVATE Ointment should be limited to 45 g per week.
DIPROVATE OINTMENT IS NOT TO BE USED WITH OCCLUSIVE DRESSINGS.
************************************************************************