BECLOMETHASONE DIPROPIONATE
DESCRIPTION:
Beclomethasone dipropionate, USP, the active component of BECLATE Inhalation
Aerosol, is an anti-inflammatory corticosteroid having the chemical name 9-
chloro-11(beta),17,21-trihydroxy- 16(beta)-methylpregna-1,4-diene-3,20-dione
17,21-dipropionate.
Beclomethasone 17,21-dipropionate is a diester of beclomethasone, a synthetic
halogenated corticosteroid.
Beclomethasone dipropionate is a white to creamy- white, odorless powder with a
molecular formula of C28H37CIO7 and a molecular weight of 521.05. It is very
slightly soluble in water, very soluble in chloroform, and freely soluble in
acetone and in alcohol.
BECLATE Inhalation Aerosol is a pressurized metered-dose aerosol unit
containing a microcrystalline suspension of beclomethasone dipropionate-
trichloromonofluoromethane clathrate in a mixture of propellants
(trichloromonofluoromethane and dichlorodifluoromethane) with oleic acid. Each
canister contains beclomethasone dipropionate- trichloromonofluoromethane
clathrate having a molecular proportion of beclomethasone dipropionate to
trichloromonofluoromethane between 3:1 and 3:2. Each actuation delivers a
quantity of clathrate equivalent to 42 mcg of beclomethasone dipropionate, USP
from the mouthpiece and 50 mcg from the valve. The contents of one 6.7-g
canister provide 80 oral inhalations, and the contents of one 16.8-g canister
provide 200 oral inhalations.
ACTIONS/CLINICAL PHARMACOLOGY:
Animal studies show that beclomethasone dipropionate has potent anti-
inflammatory activity. When beclomethasone dipropionate was administered
systemically to mice, the anti- inflammatory activity was accompanied by other
features typical of glucocorticoid action, including thymic involution, liver
glycogen deposition, and pituitary-adrenal suppression. After systemic
administration of beclomethasone dipropionate to rats, the anti-inflammatory
action was associated with little or no effect on other tests of glucocorticoid
activity.
Beclomethasone dipropionate is sparingly soluble and is poorly mobilized from
subcutaneous or intramuscular injection sites. However, systemic absorption
occurs after all routes of administration. When given to animals in the form of
an aerosolized suspension of the trichloromonofluoromethane clathrate, the drug
is deposited in the mouth and nasal passages, the trachea and principal bronchi,
and the lung; a considerable portion of the drug is also swallowed. Absorption
occurs rapidly from all respiratory and gastrointestinal tissues, as indicated
by the rapid clearance of radioactively labeled drug from local tissues and
appearance of tracer in the circulation. There is no evidence of tissue storage
of beclomethasone dipropionate or its metabolites. Lung slices can metabolize
beclomethasone dipropionate rapidly to beclomethasone 17-monopropionate and more
slowly to free beclomethasone (which has very weak anti- inflammatory activity).
However, irrespective of the route of administration (injection, oral, or
aerosol), the principal route of excretion of the drug and its metabolites is
the feces. Less than 10% of the drug and its metabolites is excreted in the
urine. In humans, 12% to 15% of an orally administered dose of beclomethasone
dipropionate was excreted in the urine as both conjugated and free metabolites
of the drug.
The precise mechanisms of glucocorticoid action in asthma are unknown.
Inflammation is recognized as an important component in the pathogenesis of
asthma. Glucocorticoids have been shown to inhibit multiple cell types (e.g.,
mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils)
and mediator production or secretion (e.g., histamine, eicosanoids,
leukotrienes, and cytokines) involved in the asthmatic response. These anti-
inflammatory actions of glucocorticoids may contribute to their efficacy in
asthma.
CLINICAL STUDIES:
CLINICAL TRIALS: The effects of beclomethasone dipropionate on HPA function have
been evaluated in adult volunteers. There was no suppression of early morning
plasma cortisol concentrations when beclomethasone dipropionate was administered
in a dose of 840 mcg/day for 1 month as an aerosol or 1000 mcg/day for 3 days by
intramuscular injection. However, partial suppression of plasma cortisol
concentration was observed when beclomethasone dipropionate was administered in
doses of 2000 mcg/day intramuscularly or 1680 mcg/day by aerosol. Immediate
suppression of plasma cortisol concentrations was observed after single doses of
4000 mcg of beclomethasone dipropionate.
In one study the effects of beclomethasone dipropionate on HPA function were
examined in patients with asthma. There was no change in basal early morning
plasma cortisol concentrations or in the cortisol responses to tetracosactrin
(ACTH 1:24) stimulation after daily aerosol administration of 336, 672, or 1008
mcg of beclomethasone dipropionate for 28 days. After daily aerosol
administration of 1344 mcg for 28 days, there was slight reduction in basal
cortisol concentrations and a statistically significant (P<.01) reduction in
plasma cortisol responses to tetracosactrin stimulation. Following 52 weeks of
aerosol treatment with 840 mcg of beclomethasone dipropionate daily, 7/115 (6%)
of patients exhibited a plasma cortisol measurement below the lower limit of
normal (150 nmol-1).
Clinical experience has shown that some patients with asthma who require
corticosteroid therapy for control of symptoms can be partially or completely
withdrawn from systemic corticosteroids if therapy with beclomethasone
dipropionate aerosol is substituted. Beclomethasone dipropionate aerosol is not
effective for all patients with asthma or at all stages of the disease in a
given patient.
INDICATIONS AND USAGE:
BECLATE Inhalation Aerosol is indicated in the maintenance treatment of asthma
as prophylactic therapy. BECLATE Inhalation Aerosol is also indicated for
asthma patients who require systemic corticosteroid administration, where adding
BECLATE Inhalation Aerosol may reduce or eliminate the need for the systemic
corticosteroids.
BECLATE Inhalation Aerosol is NOT indicated for the relief of acute
bronchospasm.
CONTRAINDICATIONS:
BECLATE Inhalation Aerosol is contraindicated in the primary treatment of
status asthmaticus or other acute episodes of asthma where intensive measures
are required.
Hypersensitivity to any of the ingredients of this preparation contraindicates
its use.
WARNINGS:
Particular care is needed in patients who
are transferred from systemically active
corticosteroids to BECLATE Inhalation
Aerosol because DEATHS DUE TO ADRENAL
INSUFFICIENCY HAVE OCCURRED IN ASTHMATIC
PATIENTS DURING AND AFTER TRANSFER FROM
SYSTEMIC CORTICOSTEROIDS TO AEROSOL
BECLOMETHASONE DIPROPIONATE. After
withdrawal from systemic corticosteroids, a
number of months are required for recovery
of hypothalamic-pituitary-adrenal (HPA)
function. During this period of HPA
suppression, patients may exhibit signs and
symptoms of adrenal insufficiency when
exposed to trauma, surgery, or infections,
particularly gastroenteritis. Although
BECLATE Inhalation Aerosol may provide
control of asthmatic symptoms during these
episodes, it does NOT provide the systemic
steroid that is necessary for coping with
these emergencies.
During periods of stress or a severe
asthmatic attack, patients who have been
withdrawn from systemic corticosteroids
should be instructed to resume systemic
steroids (in large doses) immediately and
to contact their physician for further
instruction. These patients should also be
instructed to carry a warning card
indicating that they may need supplementary
systemic steroids during periods of stress
or a severe asthma attack. To assess the
risk of adrenal insufficiency in emergency
situations, routine tests of adrenal
cortical function, including measurement of
early morning resting cortisol levels,
should be performed periodically in all
patients. An early morning resting cortisol
level may be accepted as normal only if it
falls at or near the normal mean level.
Localized infections with Candida Albicans or Aspergillus Niger have occurred in
the mouth and pharynx and occasionally in the larynx. Positive cultures for oral
Candida may be present in up to 75% of patients. Although the frequency of
clinically apparent infection is considerably lower, these infections can
develop with any inhaled corticosteroid and may require treatment with
appropriate antifungal therapy or discontinuation of treatment with BECLATE
Inhalation Aerosol.
BECLATE Inhalation Aerosol is not a bronchodilator and is not indicated for
rapid relief of bronchospasm.
Patients should be instructed to contact their physicians immediately when
episodes of asthma that are not responsive to bronchodilators occur during the
course of treatment with BECLATE Inhalation Aerosol. During such episodes,
patients may require therapy with systemic corticosteroids.
Transfer of patients from systemic corticosteroid therapy to BECLATE
Inhalation Aerosol may unmask allergic conditions previously suppressed by the
systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, and eczema.
Persons who are on drugs that suppress the immune system are more susceptible to
infections than healthy individuals. Chickenpox and measles, for example, can
have a more serious or even fatal course in nonimmune children or adults on
corticosteroids. In such children or adults who have not had these diseases,
particular care should be taken to avoid exposure. How the dose, route, and
duration of corticosteroid administration affect the risk of developing a
disseminated infection is not known. The contribution of the underlying disease
and/or prior corticosteroid treatment to the risk is also not known. If exposed
to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be
indicated. If exposed to measles, prophylaxis with pooled intramuscular
immunoglobulin (IG) may be indicated. (See the respective package inserts for
complete VZIG and IG prescribing information.) If chickenpox develops, treatment
with antiviral agents may be considered.
Avoid spraying in eyes.
PRECAUTIONS:
During withdrawal from oral corticosteroids, some patients may experience
symptoms of systemically active corticosteroid withdrawal, e.g., joint and/or
muscular pain, lassitude, and depression, despite maintenance or even
improvement of respiratory function (see DOSAGE AND ADMINISTRATION). In
responsive patients, beclomethasone dipropionate may permit control of asthmatic
symptoms without suppression of HPA function, as discussed above (see
ACTIONS/CLINICAL PHARMACOLOGY). Since beclomethasone dipropionate is absorbed
into the circulation and can be systemically active, the beneficial effects of
BECLATE Inhalation Aerosol in minimizing or preventing HPA dysfunction may be
expected only when recommended dosages are not exceeded.
Because of the possibility of systemic absorption of orally inhaled
corticosteroids, including beclomethasone, patients should be monitored for
symptoms of systemic effects such as mental disturbances, increased bruising,
weight gain, cushingoid features, acneiform lesions, and cataracts. Therefore,
if such changes occur, BECLATE Inhalation Aerosol should be discontinued
slowly, consistent with accepted procedures for discontinuing oral steroids.
A reduction of growth velocity in children or teenagers may occur as a result of
inadequate control of chronic diseases such as asthma or from use of
corticosteroids for treatment. Physicians should closely follow the growth of
adolescents taking corticosteroids by any route and weigh the benefits of
corticosteroid therapy and asthma control against the possibility of growth
suppression if an adolescent's growth appears slowed.
The long-term local and systemic effects of BECLATE Inhalation Aerosol in
human subjects are still not fully known. In particular, the effects resulting
from chronic use of BECLATE Inhalation Aerosol on developmental or immunologic
processes in the mouth, pharynx, trachea, and lung are unknown.
Inhaled corticosteroids should be used with caution, if at all, in patients with
active or quiescent tuberculosis infection of the respiratory tract; untreated
systemic fungal, bacterial, parasitic, or viral infections; or ocular herpes
simplex.
Pulmonary infiltrates with eosinophilia may occur in patients on BECLATE
Inhalation Aerosol therapy. Although it is possible that in some patients this
state may become manifest because of systemic corticosteroid withdrawal when
inhalational corticosteroids are administered, a causative role for
beclomethasone dipropionate and/or its vehicle cannot be ruled out.
INFORMATION FOR PATIENTS: Patients being treated with BECLATE Inhalation
Aerosol should receive the following information and instructions. This
information is intended to aid in the safe and effective use of this medication.
It is not a disclosure of all possible adverse or intended effects.
Patients should use BECLATE Inhalation Aerosol at regular intervals as
directed. Results of clinical trials indicated significant improvement may occur
within the first day or two of treatment; however, the full benefit may not be
achieved until treatment has been administered 1 or 2 weeks or longer. The
patient should not increase the prescribed dosage but should contact the
physician if symptoms do not improve or if the condition worsens.
Patients should be advised that BECLATE Inhalation Aerosol is not intended for
use in the treatment of acute asthma. Patients should be made aware of the
prophylactic nature of therapy with inhaled beclomethasone dipropionate and that
it should be taken regularly even when they are asymptomatic. Patients should be
instructed to contact their physicians immediately if there is any deterioration
of their asthma.
BECLATE Inhalation Aerosol should not be stopped abruptly. If discontinuing
use of BECLATE Inhalation Aerosol is necessary, the patient's physician should
be contacted immediately.
Each patient should be advised to rinse his/her mouth each time after using
BECLATE Inhalation Aerosol.
Patients should be warned to avoid exposure to chickenpox or measles. Patients
should also be advised that if they are exposed, medical advice should be sought
without delay.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: The carcinogenicity of
beclomethasone dipropionate was evaluated in rats that were exposed for a total
of 95 weeks, 13 weeks at inhalation doses up to 0.4 mg /kg and the remaining 82
weeks at combined oral and inhalation doses up to 2.4 mg/kg. There was no
evidence of carcinogenicity in this study at the highest dose, approximately 20
or 36 times the maximum recommended daily inhalation dose in adults and
children, respectively, on a mg/m(squared) basis.
Beclomethasone dipropionate did not induce gene mutation in bacterial cells or
mammalian Chinese Hamster ovary (CHO) cells in vitro. No significant clastogenic
effect was seen in cultured CHO cells in vitro or in the mouse micronucleus test
in vivo.
In rats, beclomethasone dipropionate caused decreased conception rates at an
oral dose of 16 mg/kg (approximately 130 times the maximum recommended daily
inhalation dose in adults on a mg/m(squared) basis. Inhibition of the estrous
cycle in dogs was observed following oral dosing at 0.5 mg/kg (approximately 15
times the maximum recommended daily inhalation dose in adults on a mg/m(squared)
basis). No inhibition of the estrous cycle in dogs was seen following 12 months'
exposure at an estimated daily inhalation dose of 0.33 mg/kg (approximately 9
times the maximum recommended daily inhalation dose in adults on a mg/m(squared)
basis).
PREGNANCY: TERATOGENIC EFFECTS: Pregnancy Category C. Like other
corticosteroids, beclomethasone dipropionate was teratogenic and embryocidal in
the mouse and rabbit at a subcutaneous dose of 0.1 mg/kg in mice or 0.025 mg/kg
in rabbits (approximately 1/2 the maximum recommended daily inhalation dose in
adults on a mg/m(squared) basis). No teratogenicity or embryocidal effects were
seen in rats when exposed to an inhalation dose of 0.1mg/kg plus oral doses of
up to 10 mg/kg per day for a combined dose of 10.1 mg/kg (approximately 80 times
the maximum recommended daily inhalation dose in adults on a mg/m(squared)
basis). There are no adequate and well-controlled studies in pregnant women.
BECLATE Inhalation Aerosol should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
NURSING MOTHERS: Corticosteroids are secreted in human milk. Because of the
potential for serious adverse reactions in nursing infants for BECLATE
Inhalation Aerosol, a decision should be made whether to discontinue nursing or
to discontinue the drug, taking into account the importance of the drug to the
mother.
PEDIATRIC USE: The safety and effectiveness of BECLATE Inhalation Aerosol have
been established in children aged 6 years and above. The safety and
effectiveness of BECLATE Inhalation Aerosol in children below 6 years of age
have not been established. Corticosteroids have been shown to cause a reduction
in growth velocity in children and teenagers with extended use. If a child or
teenager on any corticosteroid appears to have growth suppression, the
possibility that they are particularly sensitive to this effect of
corticosteroids should be considered (see PRECAUTIONS).
ADVERSE REACTIONS:
DEATHS DUE TO ADRENAL INSUFFICIENCY HAVE OCCURRED IN ASTHMATIC PATIENTS DURING
AND AFTER TRANSFER FROM SYSTEMIC CORTICOSTEROIDS TO AEROSOL BECLOMETHASONE
DIPROPIONATE (SEE WARNINGS).
Suppression of HPA function (reduction of early morning plasma cortisol levels)
has been reported in adult patients who received 1344-mcg daily doses of
BECLATE Inhalation Aerosol for 1 month. A few patients on BECLATE Inhalation
Aerosol have complained of hoarseness or dry mouth.
In addition, the following adverse events have been reported spontaneously
during worldwide postmarketing surveillance. Therefore, the frequency of events
and causality cannot be reliably determined. The adverse events reported in
association with BECLATE Inhalation Aerosol include:
GENERAL: Immediate and delayed hypersensitivity reactions including
anaphylactic/anaphylactoid reactions, angioedema, bronchospasm, rash, urticaria.
EAR, NOSE, AND THROAT: Dryness and irritation of the nose, throat, and mouth;
hoarseness; localized infections with Candida or Aspergillus; unpleasant taste
and smell; loss of taste and smell.
ENDOCRINE AND METABOLIC: Cushingoid features, growth velocity reduction in
children/adolescents, weight gain.
EYE: Cataracts, glaucoma, increased intraocular pressure.
GASTROINTESTINAL: Nausea, vomiting.
NERVOUS: Dizziness, headache, lightheadedness.
PSYCHIATRY: Agitation, depression, mental disturbances.
RESPIRATORY: Paradoxical bronchospasm, wheezing.
SKIN: Acneiform lesions, atrophy, bruising, pruritus, purpura, striae.
OVERDOSAGE:
For maximum doses studied in humans, see the Clinical Trials subsection. Chronic
overdosage may result in signs/symptoms of hypercorticism (see PRECAUTIONS). No
deaths occurred when beclomethasone dipropionate was given as single oral doses
of 3000 mg/kg to mice and 2000 mg/kg to rats (approximately 12000 and 16000
times, respectively, the maximum recommended human daily inhalation dose on a
mg/m(squared) basis).
DOSAGE AND ADMINISTRATION:
BECLATE INHALATION AEROSOL SHOULD BE TEST SPRAYED INTO THE AIR BEFORE USING
FOR THE FIRST TIME AND IN CASES WHERE THE PRODUCT HAS NOT BEEN USED FOR A
PROLONGED PERIOD OF TIME.
ADULTS AND CHILDREN 12 YEARS OF AGE AND OLDER: The usual recommended dosage is
two inhalations (84 mcg) given three or four times a day. Alternatively, four
inhalations (168 mcg) given twice daily have been shown to be effective in some
patients. In patients with severe asthma, it is advisable to start with 12 to 16
inhalations a day (504 to 672 mcg) and adjust the dosage downward according to
the response of the patient. THE MAXIMAL DAILY INTAKE SHOULD NOT EXCEED 20
INHALATIONS, 840 MCG (0.84 MG), IN ADULTS.
CHILDREN 6 TO 12 YEARS OF AGE: The usual recommended dosage is one or two
inhalations (42 to 84 mcg) given three or four times a day according to the
response of the patient. Alternatively, four inhalations (168 mcg) given twice
daily have been shown to be effective in some patients. THE MAXIMAL DAILY INTAKE
SHOULD NOT EXCEED 10 INHALATIONS, 420 MCG (0.42 MG), IN CHILDREN 6 TO 12 YEARS
OF AGE.
Insufficient clinical data exist with respect to the administration of BECLATE
Inhalation Aerosol in children below the age of 6.
Rinsing the mouth after inhalation is advised.
DIFFERENT CONSIDERATIONS MUST BE GIVEN TO THE FOLLOWING GROUPS OF PATIENTS IN
ORDER TO OBTAIN THE FULL THERAPEUTIC BENEFIT OF BECLATE INHALATION AEROSOL.
PATIENTS NOT RECEIVING SYSTEMIC CORTICOSTEROIDS: Patients who require
maintenance therapy of their asthma may benefit from treatment with BECLATE
Inhalation Aerosol at the doses recommended above. In patients who respond to
BECLATE Inhalation Aerosol, improvement in pulmonary function is usually
apparent within 1 to 4 weeks after the start of therapy. Once the desired effect
is achieved, consideration should be given to tapering to the lowest effective
dose.
PATIENTS MAINTAINED ON SYSTEMIC CORTICOSTEROIDS: Clinical studies have shown
that BECLATE Inhalation Aerosol may be effective in the management of
asthmatics dependent or maintained on systemic corticosteroids and may permit
replacement or significant reduction in the dosage of systemic corticosteroids.
The patient's asthma should be reasonably stable before treatment with BECLATE
Inhalation Aerosol is started. Initially, BECLATE Inhalation Aerosol should be
used concurrently with the patient's usual maintenance dose of systemic
corticosteroid. After approximately 1 week, gradual withdrawal of the systemic
corticosteroid is started by reducing the daily or alternate-daily dose.
Reductions may be made after an interval of 1 or 2 weeks, depending on the
response of the patient. Generally, these decrements should not exceed 2.5 mg of
prednisone or its equivalent. During withdrawal, some patients may experience
symptoms of systemic corticosteroid withdrawal, e.g., joint and/or muscular
pain, lassitude, and depression, despite maintenance or even improvement in
pulmonary function. Such patients should be encouraged to continue with the
inhaler but should be monitored for objective signs of adrenal insufficiency. If
evidence of adrenal insufficiency occurs, the systemic corticosteroid doses
should be increased temporarily and thereafter withdrawal should continue more
slowly.
During periods of stress or a severe asthma attack, transfer patients may
require supplementary treatment with systemic corticosteroids.
DIRECTIONS FOR USE: Illustrated Patient's Instructions for Use accompany each
package of BECLATE Inhalation Aerosol.
CONTENTS UNDER PRESSURE: Do not puncture. Do not use or store near heat or open
flame.
Exposure to temperatures above 120 deg F may cause bursting. Never throw
container into fire or incinerator. Keep out of reach of children.
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