General
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. Although suppression of HPA function
below the clinical normal range did not occur with doses of QVAR up to and
including 640 mcg/day, a dose dependent reduction of adrenal cortisol production
was observed. Since inhaled beclomethasone dipropionate is absorbed into the
circulation and can be systemically active, HPA axis suppression by QVAR could
occur when recommended doses are exceeded or in particularly sensitive
individuals. Since individual sensitivity to effects on cortisol production
exist, physicians should consider this information when prescribing QVAR.
Because of the possibility of systemic absorption of inhaled corticosteroids,
patients treated with these drugs should be observed carefully for any evidence
of systemic corticosteroid effect. Particular care should be taken in observing
patients postoperatively or during periods of stress for evidence of inadequate
adrenal response.
It is possible that systemic corticosteroid effects, such as hypercorticism
and adrenal suppression, may appear in a small number of patients, particularly
at higher doses. If such changes occur, QVAR should be reduced slowly,
consistent with accepted procedures for management of asthma symptoms and for
tapering of systemic steroids.
A 12 month randomized controlled clinical trial evaluated the effects of HFA
beclomethasone dipropionate without spacer versus CFC beclomethasone
dipropionate with large volume spacer on growth in children age 5-11. A total of
520 patients were enrolled, of whom 394 received HFA-BDP (100 – 400 mcg/day
ex-valve) and 126 received CFC-BDP (200 – 800 mcg/day ex-valve). Similar control
of asthma was noted in each treatment arm. When comparing results at month 12 to
baseline, the mean growth velocity in children treated with HFA-BDP was
approximately 0.5 cm/year less than that noted with children treated with
CFC-BDP via large volume spacer.
A reduction in growth velocity in growing children 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
all pediatric patients taking corticosteroids by any route and weigh the
benefits of corticosteroid therapy and asthma control against the possibility of
growth suppression.
The long-term and systemic effects of QVAR in humans are still not fully
known. In particular, the effects resulting from chronic use of the agent 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.
Rare instances of glaucoma, increased intraocular pressure, and cataracts
have been reported following the inhaled administration of
corticosteroids.
Information for Patients
Patients being treated with QVAR should receive the following
information and instructions. This information is intended to aid them in the
safe and effective use of this medication. It is not a disclosure of all
possible adverse or intended effects.
Persons who are on immunosuppressant doses of corticosteroids should be
warned to avoid exposure to chickenpox or measles. Patients should also be
advised that if they are exposed to these diseases, medical advice should be
sought without delay.
Patients should use QVAR at regular intervals as directed. Results of
clinical trials indicated significant improvements may occur within the first 24
hours of treatment in some patients; however, the full benefit may not be
achieved until treatment has been administered for 1 to 2 weeks, or longer. The
patient should not increase the prescribed dosage but should contact their
physician if symptoms do not improve or if the condition worsens.
Patients should be advised that QVAR is not intended for use in the treatment
of acute asthma. The patient should be instructed to contact their physician
immediately if there is any deterioration of their asthma.
Patients should be instructed on the proper use of their inhaler. Patients
may wish to rinse their mouth after QVAR use. The patient should also be advised
that QVAR may have a different taste and inhalation sensation than that of an
inhaler containing CFC propellant.
QVAR use should not be stopped abruptly. The patient should contact their
physician immediately if use of QVAR is discontinued.
For the proper use of QVAR, the patient should read and carefully follow the
accompanying Patient's Instructions.
Carcinogenesis, Mutagenesis, Impairment of
Fertility
The carcinogenicity of beclomethasone dipropionate was evaluated
in rats which were exposed for a total of 95 weeks, 13 weeks at inhalation doses
up to 0.4 mg/kg/day and the remaining 82 weeks at combined oral and inhalation
doses up to 2.4 mg/kg/day. There was no evidence of carcinogenicity in this
study at the highest dose, which is approximately 30 and 55 times the maximum
recommended daily inhalation dose in adults and children, respectively, on a
mg/m2 basis.
Beclomethasone dipropionate did not induce gene mutation in the 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/day (approximately 200 times the maximum recommended daily
inhalation dose in adults on a mg/m2 basis). Impairment
of fertility, as evidence by inhibition of the estrous cycle in dogs, was
observed following treatment by the oral route at a dose of 0.5 mg/kg/day
(approximately 20 times the maximum recommended daily inhalation dose in adults
on a mg/m2 basis). No inhibition of the estrous cycle in
dogs was seen following 12 months of exposure to beclomethasone dipropionate by
the Inhalation route at an estimated daily dose of 0.33 mg/kg (approximately 15
times the maximum recommended daily inhalation dose in adults on a mg/m2 basis).
Pregnancy
Teratogenic Effects
Pregnancy Category C
Like other corticosteroids, parenteral (subcutaneous)
beclomethasone dipropionate was teratogenic and embryocidal in the mouse and
rabbit when given at a dose of 0.1 mg/kg/day in mice or at a dose of 0.025
mg/kg/day in rabbits. These doses in mice and rabbits were approximately
one-half the maximum recommended daily inhalation dose in adults on a mg/m2 basis. No teratogenicity or embryocidal effects were seen in
rats when exposed to an inhalation dose of 15 mg/kg/day (approximately 190 times
the maximum recommended daily inhalation dose in adults on a mg/m2 basis). There are no adequate and well controlled studies in
pregnant women. Beclomethasone dipropionate should be used during pregnancy only
if the potential benefit justifies the potential risk to the fetus.
Non-teratogenic Effects
Findings of drug-related adrenal toxicity in fetuses following
administration of beclomethasone dipropionate to rats suggest that infants born
of mothers receiving substantial doses of QVAR during pregnancy should be
observed for adrenal suppression.
Nursing Mothers
Corticosteroids are secreted in human milk. Because of the
potential for serious adverse reactions in nursing infants from QVAR, 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
Eight-hundred and thirty-four children between the ages of 5 and
12 were treated with HFA beclomethasone dipropionate (HFA BDP) in clinical
trials. The safety and effectiveness of QVAR in children below 5 years of age
have not been established.
Use of QVAR with a spacer device in children less than 5 years of age is not
recommended. In vitro dose characterization studies
were performed with QVAR 40 mcg/actuation with the Optichamber and AeroChamber
Plus® spacer utilizing inspiratory flows representative of children under 5
years old. These studies indicated that the amount of medication delivered
through the spacing device decreased rapidly with increasing wait times of 5 to
10 seconds as shown in Table 1. If QVAR is used with a spacer device, it is
important to inhale immediately.
Based on the average inspiratory flow rates generated by children 6 months to
5 years old, the projected daily dose derived from QVAR 40 mcg at one puff per
day at various wait times is depicted in the table below:
TABLE 1
| Wait time, seconds | Mean medication delivery through AeroChamber, mcg/actuation (*) | Body Weight 50th percentile, kg (**) | Medication delivered per dose, mcg/kg (***) |
| Age 6 months, Flow rate 4.8 L/min | 0
| 11.5
| 7.6
| 1.2
|
| Age 2 years, Flow rate 8.2 L/min | 0
| 14.1
| 13.5
| 0.83
|
| Age 2 years, Flow rate 8.2 L/min | 5
| 5.4
| 13.5
| 0.32
|
| Age 2 years, Flow rate 8.2 L/min | 10
| 3.9
| 13.5
| 0.23
|
| Age 5 years, Flow rate 11.0 L/min | 0
| 17.5
| 18
| 0.78
|
(*) Summary Report; Pediatric Dose Characterization of QVAR with Spacer; 3M
Pharmaceutical Development, July 21, 2004.
(**) CDC Growth charts, developed by the National Center for Health Statistics in
collaboration with the National Center for Chronic Disease Prevention and Health
Promotion (2000).
(***) Includes an estimated 20% loss in the masks
(***) QVAR 40mcg in an average adult without using a spacer delivers approximately
0.4 mcg/kg, or bid, 0.8 mcg/kg/day.
Oral inhaled 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, General).
Geriatric Use
Clinical studies of QVAR did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from
younger subjects. Other reported clinical experience has not identified
differences in responses between the elderly and younger patients. In general,
dose selection for an elderly patient should be cautious, usually starting at
the low end of the dosing range, reflecting the greater frequency of decreased
hepatic, renal, or cardiac function, and of concomitant disease or other drug
therapy.
