BUDESONIDE
DESCRIPTION:
Budesonide, the active component of PULMICORT INHALER 200 mcg, is a
corticosteroid designated chemically as (RS)-11(beta), 16(alpha), 17,21-
Tetrahydroxypregna-1,4-diene- 3,20-dione cyclic 16,17-acetal with butyraldehyde.
Budesonide is provided as a mixture of two epimers (22R and 22S). The empirical
formula of budesonide is C25H34O6 and its molecular weight is 430.5.
Budesonide is a white to off-white, tasteless, odorless powder that is
practically insoluble in water and in heptane, sparingly soluble in ethanol, and
freely soluble in chloroform. Its partition coefficient between octanol and
water at pH 7.4 is 1.6 x 10(raised to the power of 3).
PULMICORT INHALER is an inhalation-driven multi-dose dry powder inhaler which
contains only micronized budesonide. Each actuation of PULMICORT INHALER
provides 200 mcg budesonide per metered dose, which delivers approximately 160
mcg budesonide from the mouthpiece (based on IN VITRO testing at 60 L/min for 2
sec). The amount of drug delivered to the lung will depend on patient factors
such as inspiratory flow (see Patient's Instructions for Use). In adult patients
with asthma (mean FEV1 2.9 L (0.8 - 5.1 L)) mean peak inspiratory flow (PIF)
through PULMICORT INHALER was 78 (40-111) L/min. Similar results (mean PIF 82
(43-125) L/min) were obtained in asthmatic children (6 to 15 years, mean FEV1
2.1 L (0.9 - 5.4 L)).
ACTIONS/CLINICAL PHARMACOLOGY:
Budesonide is an anti-inflammatory corticosteroid that exhibits potent
glucocorticoid activity and weak mineralocorticoid activity. In standard IN
VITRO and animal models, budesonide has approximately a 200-fold higher affinity
for the glucocorticoid receptor and a 1000-fold higher topical anti-inflammatory
potency than cortisol (rat croton oil ear edema assay). As a measure of systemic
activity, budesonide is 40 times more potent than cortisol when administered
subcutaneously and 25 times more potent when administered orally in the rat
thymus involution assay.
The precise mechanism of corticosteroid actions on inflammation in asthma is not
known. Corticosteroids have been shown to have a wide range of inhibitory
activities against multiple cell types (e.g., mast cells, eosinophils,
neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine,
eicosanoids, leukotrienes, and cytokines) involved in allergic and non-allergic-
mediated inflammation. These anti-inflammatory actions of corticosteroids may
contribute to their efficacy in asthma.
Studies in asthmatic patients have shown a favorable ratio between topical anti-
inflammatory activity and systemic corticosteroid effects over a wide range of
doses from PULMICORT INHALER. This is explained by a combination of a
relatively high local anti-inflammatory effect, extensive first pass hepatic
degradation of orally absorbed drug (85-95%), and the low potency of formed
metabolites (see below).
PHARMACOKINETICS
The activity of PULMICORT INHALER is due to the parent drug, budesonide. In
glucocorticoid receptor affinity studies, the 22R form was two times as active
as the 22S epimer. IN VITRO studies indicated that the two forms of budesonide
do not interconvert. The 22R form was preferentially cleared by the liver with
systemic clearance of 1.4 L/min vs. 1.0 L/min for the 22S form. The terminal
half-life, 2 to 3 hours, was the same for both epimers and was independent of
dose. In asthmatic patients, budesonide showed a linear increase in AUC and Cmax
with increasing dose after both a single dose and repeated dosing from PULMICORT
INHALER.
ABSORPTION: After oral administration of budesonide, peak plasma concentration
was achieved in about 1 to 2 hours and the absolute systemic availability was 6-
13%. In contrast, most of budesonide delivered to the lungs is systemically
absorbed. In healthy subjects, 34% of the metered dose was deposited in the
lungs (as assessed by plasma concentration method) with an absolute systemic
availability of 39% of the metered dose. Pharmacokinetics of budesonide do not
differ significantly in healthy volunteers and asthmatic patients. Peak plasma
concentrations of budesonide occurred within 30 minutes of inhalation from
PULMICORT INHALER.
DISTRIBUTION: The volume of distribution of budesonide was approximately 3 L/kg.
It was 85-90% bound to plasma proteins. Protein binding was constant over the
concentration range (1-100 nmol/L) achieved with, and exceeding, recommended
doses of PULMICORT INHALER. Budesonide showed little or no binding to
corticosteroid binding globulin. Budesonide rapidly equilibrated with red blood
cells in a concentration independent manner with a blood/plasma ratio of about
0.8.
METABOLISM: IN VITRO studies with human liver homogenates have shown that
budesonide is rapidly and extensively metabolized. Two major metabolites formed
via cytochrome P450 3A catalyzed biotransformation have been isolated and
identified as 16(alpha)-hydroxyprednisolone and 6(beta)-hydroxybudesonide. The
corticosteroid activity of each of these two metabolites is less than 1% of that
of the parent compound. No qualitative difference between IN VITRO and IN VIVO
metabolic patterns have been detected. Negligible metabolic inactivation was
observed in human lung and serum preparations.
EXCRETION: Budesonide was excreted in urine and feces in the form of
metabolites. Approximately 60% of an intravenous radiolabeled dose was recovered
in the urine. No unchanged budesonide was detected in the urine.
SPECIAL POPULATIONS: No pharmacokinetic differences have been identified due to
race, gender or advanced age.
PEDIATRIC: Following intravenous dosing in pediatric patients age 10-14 years,
plasma half- life was shorter than in adults (1.5 hrs vs 2.0 hrs in adults). In
the same population following inhalation of budesonide via a pressurized
metered-dose inhaler, absolute systemic availability was similar to that in
adults.
HEPATIC INSUFFICIENCY: Reduced liver function may affect the elimination of
corticosteroids. The pharmacokinetics of budesonide were affected by compromised
liver function as evidenced by a doubled systemic availability after oral
ingestion. The intravenous pharmacokinetics of budesonide were, however, similar
in cirrhotic patients and in healthy subjects.
DRUG-DRUG INTERACTIONS: Ketoconazole, a potent inhibitor of cytochrome P450 3A,
the main metabolic enzyme for corticosteroids, increased plasma levels of orally
ingested budesonide. At recommended doses, cimetidine had a slight but
clinically insignificant effect on the pharmacokinetics of oral budesonide.
PHARMACODYNAMICS
To confirm that systemic absorption is not a significant factor in the clinical
efficacy of inhaled budesonide, a clinical study in patients with asthma was
performed comparing 400 mcg budesonide administered via a pressurized metered
dose inhaler with a tube spacer to 1400 mcg of oral budesonide and placebo. The
study demonstrated the efficacy of inhaled budesonide but not orally ingested
budesonide despite comparable systemic levels. Thus, the therapeutic effect of
conventional doses of orally inhaled budesonide are largely explained by its
direct action on the respiratory tract.
Generally, PULMICORT INHALER has a relatively rapid onset of action for an
inhaled corticosteroid. Improvement in asthma control following inhalation of
PULMICORT INHALER can occur within 24 hours of beginning treatment although
maximum benefit may not be achieved for 1 to 2 weeks, or longer.
PULMICORT INHALER has been shown to decrease airway reactivity to various
challenge models, including histamine, methacholine, sodium metabisulfite, and
adenosine monophosphate in hyperreactive patients. The clinical relevance of
these models is not certain.
Pretreatment with PULMICORT INHALER 1600 mcg daily (800 mcg twice daily) for
2 weeks reduced the acute (early-phase reaction) and delayed (late-phase
reaction) decrease in FEV1 following inhaled allergen challenge.
The effects of PULMICORT INHALER on the hypothalamic-pituitary-adrenal (HPA)
axis were studied in 905 adults and 404 pediatric patients with asthma. For most
patients, the ability to increase cortisol production in response to stress, as
assessed by cosyntropin (ACTH) stimulation test, remained intact with PULMICORT
INHALER treatment at recommended doses. For adult patients treated with 100,
200, 400, or 800 mcg twice daily for 12 weeks, 4%, 2%, 6%, and 13% respectively,
had an abnormal stimulated cortisol response (peak cortisol <14.5 mcg/dL
assessed by liquid chromatography following short-cosyntropin test) as compared
to 8% of patients treated with placebo. Similar results were obtained in
pediatric patients. In another study in adults, doses of 400, 800 and 1600 mcg
budesonide twice daily via PULMICORT INHALER for 6 weeks were examined; 1600
mcg twice daily (twice the maximum recommended dose) resulted in a 27% reduction
in stimulated cortisol (6-hour ACTH infusion) while 10 mg prednisone resulted in
a 35% reduction. In this study, no patient on PULMICORT INHALER at doses of
400 and 800 mcg twice daily met the criterion for an abnormal stimulated
cortisol response (peak cortisol <14.5 mcg/dL assessed by liquid chromatography)
following ACTH infusion. An open-label, long-term follow-up of 1133 patients for
up to 52 weeks confirmed the minimal effect on the HPA axis (both basal and
stimulated plasma cortisol) of PULMICORT INHALER when administered at
recommended doses. In patients who had previously been oral steroid-dependent,
use of PULMICORT INHALER in recommended doses was associated with higher
stimulated cortisol response compared to baseline following 1 year of therapy.
The administration of budesonide via PULMICORT INHALER in doses up to 800
mcg/day (mean daily dose 445 mcg/day) or via a pressurized metered- dose inhaler
in doses up to 1200 mcg/day (mean daily dose 620 mcg/day) to 216 pediatric
patients (age 3 to 11 years) for 2 to 6 years had no significant effect on
statural growth compared with non-corticosteroid therapy in 62 matched control
patients. However, the long-term effect of PULMICORT INHALER on growth is not
fully known.
CLINICAL STUDIES:
The therapeutic efficacy of PULMICORT INHALER has been evaluated in
controlled clinical trials involving more than 1300 patients (6 years and older)
with asthma of varying disease duration (<1 year to >20 years) and severity.
Double-blind, parallel, placebo-controlled clinical trials of 12 weeks duration
and longer have shown that, compared with placebo, PULMICORT INHALER
significantly improved lung function (measured by PEF and FEV1), significantly
decreased morning and evening symptoms of asthma, and significantly reduced the
need for as needed inhaled (beta)2-agonist use at doses of 400 mcg to 1600 mcg
per day (200 mcg to 800 mcg twice daily) in adults and 400 mcg to 800 mcg per
day (200 mcg to 400 mcg twice daily) in pediatric patients 6 years of age and
older.
Improved lung function (morning PEF) was observed within 24 hours of initiating
treatment in both adult and pediatric patients 6 years of age and older,
although maximum benefit was not achieved for 1 to 2 weeks, or longer, after
starting treatment. Improved lung function was maintained throughout the 12
weeks of the double-blind portion of the trials.
PATIENTS NOT RECEIVING CORTICOSTEROID THERAPY
In a 12-week clinical trial in 273 patients with mild to moderate asthma (mean
baseline FEV1 2.27 L) who were not well controlled by bronchodilators alone,
PULMICORT INHALER was evaluated at doses of 200 mcg twice daily and 400 mcg
twice daily versus placebo. The FEV1 results from this trial are shown in the
figure below. Pulmonary function improved significantly on both doses of
PULMICORT INHALER compared with placebo.
Click here for illustration(s).
In a 12-month controlled trial in 75 patients not previously receiving
corticosteroids, PULMICORT INHALER at 200 mcg twice daily resulted in
improved lung function (measured by PEF) and reduced bronchial hyperreactivity
compared to placebo.
PATIENTS PREVIOUSLY MAINTAINED ON INHALED CORTICOSTEROIDS
The safety and efficacy of PULMICORT INHALER was also evaluated in adult and
pediatric patients (age 6 to 18 years) previously maintained on inhaled
corticosteroids (adults: N = 473, mean baseline FEV1 2.04 L, baseline doses of
beclomethasone dipropionate 126-1008 mcg/day; pediatrics: N = 404, mean baseline
FEV1 2.09 L, baseline doses of beclomethasone dipropionate 126-672 mcg/day or
triamcinolone acetonide 300-1800 mcg/day). The FEV1 results of these two trials,
both 12 weeks in duration, are presented in the following figures. Pulmonary
function improved significantly with all doses of PULMICORT INHALER compared
to placebo in both trials.
Click here for illustration(s).
PATIENTS PREVIOUSLY MAINTAINED ON ORAL CORTICOSTEROIDS
In a clinical trial in 159 severe asthmatic patients requiring chronic oral
prednisone therapy (mean baseline prednisone dose 19.3 mg/day) PULMICORT
INHALER at doses of 400 mcg twice daily and 800 mcg twice daily was compared
to placebo over a 20-week period. Approximately two-thirds (68% on 400 mcg twice
daily and 64% on 800 mcg twice daily) of PULMICORT INHALER-treated patients
were able to achieve sustained (at least 2 weeks) oral corticosteroid cessation
(compared with 8% of placebo-treated patients) and improved asthma control. The
average oral corticosteroid dose was reduced by 83% on 400 mcg twice daily and
79% on 800 mcg twice daily for PULMICORT INHALER- treated patients vs. 27%
for placebo. Additionally, 58 out of 64 patients (91%) who completely eliminated
oral corticosteroids during the double-blind phase of the trial remained off
oral corticosteroids for an additional 12 months while receiving PULMICORT
INHALER.
INDICATIONS AND USAGE:
PULMICORT INHALER is indicated for the maintenance treatment of asthma as
prophylactic therapy in adult and pediatric patients six years of age or older.
It is also indicated for patients requiring oral corticosteroid therapy for
asthma. Many of those patients may be able to reduce or eliminate their
requirement for oral corticosteroids over time.
PULMICORT INHALER is NOT indicated for the relief of acute bronchospasm.
CONTRAINDICATIONS:
PULMICORT INHALER is contraindicated in the primary treatment of status
asthmaticus or other acute episodes of asthma where intensive measures are
required.
Hypersensitivity to budesonide contraindicates the use of PULMICORT INHALER.
WARNINGS:
Particular care is needed for patients who
are transferred from systemically active
corticosteroids to PULMICORT INHALER
because deaths due to adrenal insufficiency
have occurred in asthmatic patients during
and after transfer from systemic
corticosteroids to less systemically
available inhaled corticosteroids. After
withdrawal from systemic corticosteroids, a
number of months are required for recovery
of HPA function.
Patients who have been previously
maintained on 20 mg or more per day of
prednisone (or its equivalent) may be most
susceptible, particularly when their
systemic corticosteroids have been almost
completely withdrawn. During this period of
HPA suppression, patients may exhibit signs
and symptoms of adrenal insufficiency when
exposed to trauma, surgery, or infection
(particularly gastroenteritis) or other
conditions associated with severe
electrolyte loss. Although PULMICORT
INHALER may provide control of asthma
symptoms during these episodes, in
recommended doses it supplies less than
normal physiological amounts of
glucocorticoid systemically and does NOT
provide the mineralocorticoid activity that
is necessary for coping with these
emergencies.
During periods of stress or a severe asthma
attack, patients who have been withdrawn
from systemic corticosteroids should be
instructed to resume oral corticosteroids
(in large doses) immediately and to contact
their physicians for further instruction.
These patients should also be instructed to
carry a medical identification card
indicating that they may need supplementary
systemic corticosteroids during periods of
stress or a severe asthma attack.
Transfer of patients from systemic corticosteroid therapy to PULMICORT
INHALER may unmask allergic conditions previously suppressed by the systemic
corticosteroid therapy, e.g., rhinitis, conjunctivitis, and eczema (See Dosage
and Administration).
Patients who are on drugs which suppress the immune system are more susceptible
to infection than healthy individuals. Chicken pox and measles, for example, can
have a more serious or even fatal course in susceptible pediatric patients or
adults on immunosuppressant doses of corticosteroids. In pediatric or adult
patients who have not had these diseases, particular care should be taken to
avoid exposure. How the dose, route and duration of corticosteroid
administration affects 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, therapy with varicella
zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as
appropriate, may be indicated. If exposed to measles, prophylaxis with pooled
intramuscular immunoglobulin (IG) may be indicated. (See the respective package
insert for complete VZIG and IG prescribing information.) If chicken pox
develops, treatment with antiviral agents may be considered.
PULMICORT INHALER is not a bronchodilator and is not indicated for rapid
relief of bronchospasm or other acute episodes of asthma.
As with other inhaled asthma medications, bronchospasm, with an immediate
increase in wheezing, may occur after dosing. If bronchospasm occurs following
dosing with PULMICORT INHALER, it should be treated immediately with a fast-
acting inhaled bronchodilator. Treatment with PULMICORT INHALER should be
discontinued and alternate therapy instituted.
Patients should be instructed to contact their physician immediately when
episodes of asthma not responsive to their usual doses of bronchodilators occur
during treatment with PULMICORT INHALER. During such episodes, patients may
require therapy with oral corticosteroids.
PRECAUTIONS:
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.
PULMICORT INHALER will often permit control of asthma symptoms with less
suppression of HPA function than therapeutically equivalent oral doses of
prednisone. Since budesonide is absorbed into the circulation and can be
systemically active at higher doses, the full beneficial effects of PULMICORT
INHALER in minimizing HPA dysfunction may be expected only when recommended
dosages are not exceeded and individual patients are titrated to the lowest
effective dose. Since individual sensitivity to effects on cortisol production
exists, physicians should consider this information when prescribing PULMICORT
INHALER.
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 effects. 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, PULMICORT INHALER should be reduced
slowly, consistent with accepted procedures for management of asthma symptoms
and for tapering of systemic 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.
Although patients in clinical trials have received PULMICORT INHALER on a
continuous basis for periods of 1 to 2 years, the long-term local and systemic
effects of PULMICORT INHALER in human subjects are not completely known. In
particular, the effects resulting from chronic use of PULMICORT INHALER on
developmental or immunological processes in the mouth, pharynx, trachea, and
lung are unknown.
In clinical trials with PULMICORT INHALER, localized infections with Candida
albicans occurred in the mouth and pharynx in some patients. If oropharyngeal
candidiasis develops, it should be treated with appropriate local or systemic
(i.e., oral) antifungal therapy while still continuing with PULMICORT INHALER
therapy, but at times therapy with PULMICORT INHALER may need to be
temporarily interrupted under close medical supervision.
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, viral or parasitic infections; or ocular herpes
simplex.
Rare instances of glaucoma, increased introcular pressure, and cataracts have
been reported following the inhaled administration of corticosteroids.
INFORMATION FOR PATIENTS: For proper use of PULMICORT INHALER and to attain
maximum improvement, the patient should read and follow the accompanying
Patient's Instructions for Use carefully. In addition, patients being treated
with PULMICORT INHALER should receive the following information and
instructions. This information is intended to aid the patient in the safe and
effective use of the medication. It is not a disclosure of all possible adverse
or intended effects.
-- Patients should take the medication as directed and use PULMICORT INHALER
at regular intervals twice daily since its effectiveness depends on regular use.
The patient should not alter the prescribed dosage unless advised to do so by
the physician.
-- PULMICORT INHALER is not a bronchodilator and is not intended to treat
acute or life- threatening episodes of asthma.
-- PULMICORT INHALER must be in the upright position (mouthpiece on top)
during loading in order to provide the correct dose. PULMICORT INHALER must
be primed when the unit is used for the very first time. To prime the unit, hold
the unit in an upright position and turn the brown grip fully to the right, then
fully to the left until it clicks. Repeat. The unit is now primed and ready to
load the first dose by turning the grip fully to the right and fully to the left
until it clicks.
On subsequent uses, it is not necessary to prime the unit. However, it must be
loaded in the upright position immediately prior to use. Turn the brown grip
fully to the right, then fully to the left until it clicks. During inhalation,
PULMICORT INHALER must be held in the upright (mouthpiece up) or horizontal
position. Do not shake the inhaler. Place the mouthpiece between lips and inhale
forcefully and deeply. The powder is then delivered to the lungs.
-- Patients should not exhale through PULMICORT INHALER.
-- Due to the small volume of powder, the patient may not taste or sense the
presence of any medication entering the lungs when inhaling from INHALER.
This lack of "sensation" does not indicate that the patient is not receiving
benefit from PULMICORT INHALER.
-- Rinsing the mouth with water without swallowing after each dosing may
decrease the risk of the development of oral candidiasis.
-- When there are 20 doses remaining in PULMICORT INHALER, a red mark will
appear in the indicator window.
-- PULMICORT INHALER should not be used with a spacer.
-- The mouthpiece should not be bitten or chewed.
-- The cover should be replaced securely after each opening.
-- Keep PULMICORT INHALER clean and dry at all times.
-- Improvement in asthma control following inhalation of PULMICORT INHALER
can occur within 24 hours of beginning treatment although maximum benefit may
not be achieved for 1 to 2 weeks, or longer. If symptoms do not improve in that
time frame, or if the condition worsens, the patient should be instructed to
contact the physician.
-- Patients should be warned to avoid exposure to chicken pox or measles and if
they are exposed, to consult their physicians without delay.
-- For proper use of PULMICORT INHALER and to attain maximum improvement, the
patient should read and follow the accompanying Patient's Instructions for Use.
DRUG INTERACTIONS: In clinical studies, concurrent administration of budesonide
and other drugs commonly used in the treatment of asthma has not resulted in an
increased frequency of adverse events. Ketoconazole, a potent inhibitor of
cytochrome P450 3A, may increase plasma levels of budesonide during concomitant
dosing. The clinical significance of concomitant administration of ketoconazole
with PULMICORT INHALER is not known, but caution may be warranted.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: Long-term studies were
conducted in mice and rats using oral administration to evaluate the
carcinogenic potential of budesonide.
There was no evidence of a carcinogenic effect when budesonide was administered
orally for 91 weeks to mice at doses up to 200 mcg/kg/day (approximately 1/2 the
maximum recommended human daily inhalation dose on a mcg/m(squared) basis).
In a 104-week carcinogenicity study in Sprague- Dawley rats, a statistically
significant increase in the incidence of gliomas was observed in male rats
receiving oral doses of 50 mcg/kg/day (approximately 1/4 the maximum recommended
human daily inhalation dose on a mcg/m(squared) basis); no such changes were
seen in male rats receiving oral doses of 10 and 25 mcg/kg/day (approximately
1/20 and 1/8 the maximum recommended human daily inhalation dose on a
mcg/m(squared) basis) or in female rats at oral doses up to 50 mcg/kg/day
(approximately 1/4 the maximum recommended human daily inhalation dose on a
mcg/m(squared) basis).
Two additional 104-week carcinogenicity studies have been performed with oral
budesonide at doses of 50 mcg/kg/day (approximately 1/4 the maximum recommended
human daily inhalation dose on a mcg/m(squared) basis) in male Sprague-Dawley
and Fischer rats. These studies did not demonstrate an increased glioma
incidence in budesonide- treated animals as compared with concurrent controls or
reference corticosteroid-treated groups (prednisolone and triamcinolone
acetonide). Compared with concurrent controls, a statistically significant
increase in the incidence of hepatocellular tumors was observed in all three
steroid groups (budesonide, prednisolone, triamcinolone acetonide) in these
studies.
The mutagenic potential of budesonide was evaluated in six different test
systems; Ames Salmonella/microsome plate test, mouse micronucleus test, mouse
lymphoma test, chromosome aberration test in human lymphocytes, sex-linked
recessive lethal test in Drosophila melanogaster, and DNA repair analysis in rat
hepatocyte culture. Budesonide was not mutagenic or clastogenic in any of these
tests.
The effect of subcutaneous budesonide on fertility and general reproductive
performance was studied in rats. At 20 mcg/kg/day (approximately 1/10 the
maximum recommended human daily inhalation dose on a mcg/m(squared) basis),
decreases in maternal body weight gain, prenatal viability, and viability of the
young at birth and during lactation were observed. No such effects were noted at
5 mcg/kg (approximately 1/40 the maximum recommended human daily inhalation dose
on a mcg/m(squared) basis).
PREGNANCY: TERATOGENIC EFFECTS: Pregnancy Category C: As with other
glucocorticoids, budesonide produced fetal loss, decreased pup weight and
skeletal abnormalities at subcutaneous doses of 25 mcg/kg/day (approximately 1/4
the maximum recommended human daily inhalation dose on a mcg/m(squared) basis)
in rabbits and 500 mcg/kg/day (approximately 21/2 times the maximum recommended
human daily inhalation dose on a mcg/m(squared) basis) in rats.
No teratogenic or embryocidal effects were observed in rats when budesonide was
administered by inhalation at doses of 100 to 250 mcg/kg/day (approximately 1/2
to 11/4 times the maximum recommended human daily inhalation dose on a
mcg/m(squared) basis).
There are no adequate and well-controlled studies in pregnant women. Budesonide
should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Experience with oral corticosteroids since their introduction in pharmacologic
as opposed to physiologic doses suggests that rodents are more prone to
teratogenic effects from corticosteroids than humans.
NONTEROTOGENIC EFFECTS: Hypoadrenalism may occur in infants born of mothers
receiving corticosteroids during pregnancy. Such infants should be carefully
observed.
NURSING MOTHERS: Corticosteroids are secreted in human milk. Because of the
potential for adverse reactions in nursing infants from any corticosteroid, a
decision should be made whether to discontinue nursing or discontinue the drug,
taking into account the importance of the drug to the mother. Actual data for
budesonide are lacking.
PEDIATRIC USE: Safety and effectiveness of PULMICORT INHALER in pediatric
patients below 6 years of age have not been established.
In pediatric asthma patients the frequency of adverse events observed with
PULMICORT INHALER was similar between the 6- to 12-year age group (N = 172)
compared with the 13- to 17-year age group (N = 124).
Oral corticosteroids have been shown to cause growth suppression in pediatric
and adolescent patients, particularly with higher doses over extended periods.
If a pediatric or adolescent patient 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).
GERIATRIC USE: One hundred patients 65 years or older were included in the US
and non-US controlled clinical trials of PULMICORT INHALER. There were no
differences in the safety and efficacy of the drug compared to those seen in
younger patients.
DRUG INTERACTIONS:
In clinical studies, concurrent administration of budesonide and other drugs
commonly used in the treatment of asthma has not resulted in an increased
frequency of adverse events. Ketoconazole, a potent inhibitor of cytochrome P450
3A, may increase plasma levels of budesonide during concomitant dosing. The
clinical significance of concomitant administration of ketoconazole with
PULMICORT INHALER is not known, but caution may be warranted.
(See also PRECAUTIONS.) DRUG-DRUG INTERACTIONS: Ketoconazole, a potent inhibitor
of cytochrome P450 3A, the main metabolic enzyme for corticosteroids, increased
plasma levels of orally ingested budesonide. At recommended doses, cimetidine
had a slight but clinically insignificant effect on the pharmacokinetics of oral
budesonide.
(See also ACTIONS/CLINICAL PHARMACOLOGY, Pharmacokinetics.)
ADVERSE REACTIONS:
The following adverse reactions were reported in patients treated with PULMICORT
INHALER.
The incidence of common adverse events is based upon double-blind, placebo-
controlled US clinical trials in which 1,116 adult and pediatric patients age 6-
70 years (472 females and 644 males) were treated with PULMICORT INHALER (200
to 800 mcg twice daily for 12 to 20 weeks) or placebo.
The following table shows the incidence of adverse events in patients previously
receiving bronchodilators and/or inhaled corticosteroids in US controlled
clinical trials. This population included 232 male and 62 female pediatric
patients (age 6 to 17 years) and 332 male and 331 female adult patients (age 18
years and greater).
ADVERSE EVENTS WITH (>/=) 3% INCIDENCE REPORTED BY
PATIENTS ON PULMICORT INHALER
---------------------³----------³--------------------------------------------
³ ³ PULMICORT INHALER
³ ³--------------------------------------------
Adverse Event ³ Placebo ³ 200 mcg 400 mcg 800 mcg
³ N=284 ³ twice daily twice daily twice daily
³ % ³ N=286 N=289 N=98
³ ³ % % %
---------------------------------------------------------------------------------------------------
Respiratory System
Respiratory infection 17 20 24 19
Pharyngitis 9 10 9 5
Sinusitis 7 11 7 2
Voice alteration 0 1 2 6
Body As A Whole
Headache 7 14 13 14
Flu syndrome 6 6 6 14
Pain 2 5 5 5
Back pain 1 2 3 6
Fever 2 2 4 0
Digestive System
Oral candidiasis 2 2 4 4
Dyspepsia 2 1 2 4
Gastroenteritis 1 1 2 3
Nausea 2 2 1 3
Average Duration
of Exposure (days) 59 79 80 80
The table above includes all events (whether considered drug-related or non
drug-related by the investigators) that occurred at a rate of (>/=)3% in any one
PULMICORT INHALER group and were more common than in the placebo group. In
considering these data, the increased average duration of exposure for PULMICORT
INHALER patients should be taken into account.
The following other adverse events occurred in these clinical trials using
PULMICORT INHALER with an incidence of 1 to 3% and were more common on
PULMICORT INHALER than on placebo.
Body As A Whole: neck pain
Cardiovascular: syncope
Digestive: abdominal pain, dry mouth, vomiting
Metabolic and Nutritional: weight gain
Musculoskeletal: fracture, myalgia
Nervous: hypertonia, migraine
Platelet, Bleeding and Clotting: ecchymosis
Psychiatric: insomnia
Resistance Mechanisms: infection
Special Senses: taste perversion
In a 20-week trial in adult asthmatics who previously required oral
corticosteroids, the effects of PULMICORT INHALER 400 mcg twice daily (N=53)
and 800 mcg twice daily (N=53) were compared with placebo (N=53) on the
frequency of reported adverse events. Adverse events, whether considered drug-
related or non drug-related by the investigators, reported in more than five
patients in the PULMICORT INHALER group and which occurred more frequently
with PULMICORT INHALER than placebo are shown below (% PULMICORT INHALER
and % placebo). In considering these data, the increased average duration of
exposure for PULMICORT INHALER patients (78 days for PULMICORT INHALER vs.
41 days for placebo) should be taken into account.
Body As A Whole: asthenia (9% and 2%)
headache (12% and 2%)
pain (10% and 2%)
Digestive: dyspepsia (8% and 0%)
nausea (6% and 0%)
oral candidiasis (10% and 0%)
Musculoskeletal: arthralgia (6% and 0%)
Respiratory: cough increased (6% and 2%)
respiratory infection (32% and 13%)
rhinitis (6% and 2%)
sinusitis (16% and 11%)
PEDIATRIC STUDIES: In a 12-week placebo- controlled trial in 404 pediatric
patients 6 to 18 years of age previously maintained on inhaled corticosteroids,
the frequency of adverse events for each age category (6 to 12 years, 13 to 18
years) was comparable for PULMICORT INHALER (at 100, 200 and 400 mcg twice
daily) and placebo. There were no clinically relevant differences in the pattern
or severity of adverse events in children compared with those reported in
adults.
ADVERSE EVENT REPORTS FROM OTHER SOURCES: Rare adverse events reported in the
published literature or from marketing experience include: immediate and delayed
hypersensitivity reactions including rash, contact dermatitis, urticaria,
angioedema and bronchospasm; symptoms of hypocorticism and hypercorticism;
psychiatric symptoms including depression, aggressive reactions, irritability,
anxiety and psychosis.
OVERDOSAGE:
The potential for acute toxic effects following overdose of PULMICORT INHALER
is low. If used at excessive doses for prolonged periods, systemic
corticosteroid effects such as hypercorticism may occur (see PRECAUTIONS).
PULMICORT INHALER at twice the highest recommended dose (3200 mcg daily)
administered for 6 weeks caused a significant reduction (27%) in the plasma
cortisol response to a 6-hour infusion of ACTH compared with placebo (+1%). The
corresponding effect of 10 mg prednisone daily was a 35% reduction in the plasma
cortisol response to ACTH.
The minimal inhalation lethal dose in mice was 100 mg/kg (approximately 250
times the maximum recommended human daily inhalation dose on a mcg/m(squared)
basis). There were no deaths following the administration of an inhalation dose
of 68 mg/kg in rats (approximately 345 times the maximum recommended human
daily inhalation dose on a mcg/m(squared) basis). The minimal oral lethal dose
was 200 mg/kg in mice and less than 100 mg/kg in rats (approximately 500 times
the maximum recommended human daily inhalation dose on a mcg/m(squared) basis).
DOSAGE AND ADMINISTRATION:
PULMICORT INHALER should be administered by the orally inhaled route in
asthmatic patients age 6 years and older. Individual patients will experience a
variable onset and degree of symptom relief. Generally, PULMICORT INHALER has
a relatively rapid onset of action for an inhaled corticosteroid. Improvement in
asthma control following inhaled administration of PULMICORT INHALER can
occur within 24 hours of initiation of treatment, although maximum benefit may
not be achieved for 1 to 2 weeks, or longer. The safety and efficacy of
PULMICORT INHALER when administered in excess of recommended doses have not
been established.
The recommended starting dose and the highest recommended dose of PULMICORT
INHALER, based on prior asthma therapy, are listed in the following table.
----------------------------------------------------------------------------------------------------------------------------------------------
Previous Recommended Highest
Therapy Starting dose Recommended dose
----------------------------------------------------------------------------------------------------------------------------------------------
Adults: Bronchodilators alone 200 to 400 mcg twice daily 400 mcg twice daily
Inhaled Corticosteroids 200 to 400 mcg twice daily 800 mcg twice daily
Oral Corticosteroids 400 to 800 mcg twice daily 800 mcg twice daily
------------------------------------------------------------------------------
Children: Bronchodilators alone 200 mcg twice daily 400 mcg twice daily
Inhaled Corticosteroids 200 mcg twice daily 400 mcg twice daily
Oral Corticosteroids The highest recommended dose in children
is 400 mcg twice daily
PATIENTS MAINTAINED ON CHRONIC ORAL CORTICOSTEROIDS
Initially, PULMICORT INHALER should be used concurrently with the patient's
usual maintenance dose of systemic corticosteroid. After approximately one
week, gradual withdrawal of the systemic corticosteroid is started by reducing
the daily or alternate daily dose. The next reduction is made after an interval
of one or two weeks, depending on the response of the patient. Generally, these
decrements should not exceed 2.5mg of prednisone or its equivalent. A slow rate
of withdrawal is strongly recommended. During reduction of oral corticosteroids,
patients should be carefully monitored for asthma instability, including
objective measures of airway function, and for adrenal insufficiency (see
WARNINGS). 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 PULMICORT 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.
NOTE: In all patients it is desirable to titrate to the lowest effective dose
once asthma stability is achieved.
Patients should be instructed to prime PULMICORT INHALER prior to its initial
use, and instructed to inhale deeply and forcefully each time the unit is used.
Rinsing the mouth after inhalation is also recommended.
DIRECTIONS FOR USE: Illustrated Patient's Instructions for Use accompany each
package of PULMICORT INHALER.
PATIENT PACKAGE INSERT:
Please read this leaflet carefully before you start to take your medicine. It
provides a summary of information on your medicine.
FOR FURTHER INFORMATION ASK YOUR DOCTOR OR PHARMACIST.
WHAT YOU SHOULD KNOW ABOUT PULMICORT INHALER(R)
Your doctor has prescribed Pulmicort Inhaler 200 mcg. It contains a
medication called budesonide, which is a synthetic corticosteroid.
Corticosteroids are natural substances found in the body that help fight
inflammation. They are used to treat asthma because they reduce the swelling and
irritation in the walls of the small air passages in the lungs and ease
breathing problems. When inhaled regularly, corticosteroids also help to prevent
attacks of asthma.
Pulmicort Inhaler treats the inflammation-the "quiet part" of asthma that you
cannot hear, see, or feel. When inflammation is left untreated, your asthma
symptoms and attacks can increase. Pulmicort Inhaler works to prevent and
reduce your asthma symptoms and attacks.
IMPORTANT POINTS TO REMEMBER ABOUT PULMICORT INHALER
1. MAKE SURE that this medicine is suitable for you (see "BEFORE USING YOUR
PULMICORT INHALER" below).
2. It is important that you inhale each dose as your doctor has advised.
3. Use your Inhaler as directed by your doctor. DO NOT STOP TREATMENT OR
REDUCE YOUR DOSE EVEN IF YOU FEEL BETTER, unless told to do so by your doctor.
4. DO NOT inhale more doses or use your Inhaler more often than instructed by
your doctor.
5. This medicine is NOT intended to provide rapid relief of your breathing
difficulties during an asthma attack. It must be taken at regular intervals as
recommended by your doctor, and not as an emergency measure.
6. Your doctor may prescribe additional medication (such as bronchodilators) for
emergency relief if an acute asthma attack occurs. Please contact your doctor
if:
-> an asthma attack does not respond to the additional medication,
-> you require more of the additional medication than usual.
7. If you also use another medicine by inhalation, you should consult your
doctor for instructions on when to use it in relation to using your Pulmicort
Inhaler.
BEFORE USING YOUR PULMICORT INHALER
TELL YOUR DOCTOR BEFORE STARTING TO TAKE THIS MEDICINE:
-> if you are pregnant (or intending to become pregnant),
-> if you are breast-feeding a baby,
-> if you are allergic to budesonide or any other orally inhaled corticosteroid.
In some circumstances, this medicine may not be suitable and your doctor may
wish to give you a different medicine. Make sure that your doctor knows what
other medicines you are taking.
USING YOUR PULMICORT INHALER
-> Follow the instructions shown on the other side. If you have any problems,
tell your doctor or pharmacist.
-> It is important that you inhale each dose as directed by your doctor. The
pharmacy label will usually tell you what dose to take and how often. If it
doesn't, or you are not sure, ask your doctor or pharmacist.
DOSAGE
-> Use as directed by your doctor.
-> It is VERY IMPORTANT that you follow your doctor's instructions as to how
many inhalations to take and how often to use your Pulmicort Inhaler.
-> DO NOT inhale more doses or use your Pulmicort Inhaler more often than
your doctor advises.
-> It may take 1 to 2 weeks or longer before you feel maximum improvement, so IT
IS VERY IMPORTANT THAT YOU USE PULMICORT INHALER REGULARLY. DO NOT STOP
TREATMENT OR REDUCE YOUR DOSE EVEN IF YOU ARE FEELING BETTER, unless told to do
so by your doctor.
-> If you miss a dose, just take your regularly scheduled next dose when it is
due. DO NOT DOUBLE the dose.
HOW TO USE YOUR PULMICORT INHALER(R)
Read the complete instructions carefully and use only as directed.
BEFORE YOU USE A NEW PULMICORT INHALER
Before you use a new Pulmicort Inhaler for the first time, you should prime
it. To do this, turn the cover and lift off. Hold Pulmicort Inhaler upright
(with mouthpiece up), then twist the brown grip fully to the right and back
again to the left. Repeat. Now you are ready to use it.
YOU DO NOT HAVE TO PRIME IT ANY OTHER TIME AFTER THIS, EVEN IF YOU PUT IT ASIDE
FOR A PROLONGED PERIOD OF TIME.
FOLLOW THE INSTRUCTIONS BELOW:
Click here for illustration(s).
1. LOADING A DOSE
-> Twist the cover and lift off.
-> In order to provide the correct dose, PULMICORT INHALER MUST BE HELD IN
THE UPRIGHT POSITION (MOUTHPIECE UP) WHENEVER A DOSE OF MEDICATION IS BEING
LOADED.
-> Twist the brown grip fully to the right as far as it will go. Twist it back
again fully to the left.
Click here for illustration(s).
-> You will hear a click.
-> Turn your head away from the inhaler and breathe out. DO NOT BLOW OR EXHALE
INTO THE INHALER. DO NOT SHAKE THE INHALER AFTER LOADING IT.
Click here for illustration(s).
2. INHALING THE DOSE
-> When you are inhaling, Pulmicort Inhaler MUST be held in the upright
(mouthpiece up) or horizontal position.
-> Place the mouthpiece between your lips and inhale deeply and forcefully.
-> If more than one dose is required, just repeat the steps above.
-> WHEN YOU ARE FINISHED, PLACE THE COVER BACK ON the inhaler and twist shut.
RINSE YOUR MOUTH WITH WATER. DO NOT SWALLOW.
-> KEEP YOUR PULMICORT INHALER CLEAN AND DRY AT ALL TIMES.
STORING YOUR PULMICORT INHALER
-> After each use, place the white cover back on and twist it firmly into place.
-> Keep Pulmicort Inhaler in a dry place at controlled room temperature,
68deg to 77degF (20deg to 25degC).
-> Keep your Pulmicort Inhaler out of the REACH OF YOUNG CHILDREN.
-> DO NOT use after the date shown on the body of your Inhaler.
HOW TO KNOW WHEN YOUR PULMICORT INHALER IS EMPTY
THERE ARE 200 DOSES IN EACH PULMICORT INHALER.
Your Pulmicort Inhaler has a convenient dose indicator window just below the
mouthpiece. Click here for illustration(s).
-> WHEN A RED MARK APPEARS AT THE TOP OF THE WINDOW, THERE ARE 20 DOSES OF
MEDICINE REMAINING.
Now is the time to get your next Pulmicort Inhaler.
-> WHEN THE RED MARK REACHES THE BOTTOM OF THE WINDOW, YOUR INHALER IS EMPTY.
DISCARD IT. (You may still hear a sound if you shake it-this sound is not the
medicine. This sound is produced by the drying agent inside Inhaler.)
-> DO NOT IMMERSE IT IN WATER TO FIND OUT IF IT IS EMPTY. SIMPLY CHECK YOUR DOSE
INDICATOR WINDOW.
FURTHER INFORMATION ABOUT PULMICORT INHALER
-> Pulmicort Inhaler delivers your medicine as a very fine powder THAT YOU
MAY NOT TASTE, SMELL, OR FEEL. By following the instructions for use in this
leaflet, you can be confident that you have received the correct dose.
-> Pulmicort Inhaler should not be used with a spacer.
-> Pulmicort Inhaler contains only budesonide and does not contain any
inactive ingredients.
-> Pulmicort Inhaler is specially designed to deliver only one dose at a
time, no matter how often you click the brown grip. If you accidentally blow
into your inhaler after loading a dose, simply follow the instructions for
loading a new dose.
THIS LEAFLET DOES NOT CONTAIN THE COMPLETE INFORMATION ABOUT YOUR MEDICINE. IF
YOU HAVE ANY QUESTIONS, OR ARE NOT SURE ABOUT SOMETHING, THEN YOU SHOULD ASK
YOUR DOCTOR OR PHARMACIST.
YOU MAY WANT TO READ THIS LEAFLET AGAIN. PLEASE DO NOT THROW IT AWAY UNTIL YOU
HAVE FINISHED YOUR MEDICINE.
REMEMBER: THIS MEDICINE HAS BEEN PRESCRIBED FOR YOU BY YOUR DOCTOR. DO NOT GIVE
THIS MEDICINE TO ANYONE ELSE.
USE THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE BY YOUR DOCTOR.
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