Included as part of the PRECAUTIONS section.
Local Effects Of Inhaled Corticosteroids
In clinical trials, the development of localized
infections of the mouth and pharynx with Candida albicans has occurred
in subjects treated with FLOVENT HFA. When such an infection develops, it should
be treated with appropriate local or systemic (i.e., oral) antifungal therapy
while treatment with FLOVENT HFA continues, but at times therapy with FLOVENT
HFA may need to be interrupted. Advise the patient to rinse his/her mouth with
water without swallowing following inhalation to help reduce the risk of
Acute Asthma Episodes
FLOVENT HFA is not to be regarded as 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
FLOVENT HFA. During such episodes, patients may require therapy with oral
Persons who are using 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
susceptible children or adults using corticosteroids. In such children or
adults who have not had these diseases or been properly immunized, particular
care should be taken to avoid exposure. How the dose, route, and duration of
corticosteroid administration affect the risk of developing a disseminatedÂ infection
is not known. The contribution of the underlying disease and/or prior
corticosteroid treatment to the risk is also not known. If a patient is exposed
to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be
indicated. If a patient is 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.
Inhaled corticosteroids should be used with caution, if
at all, in patients with active or quiescent tuberculosis infections of the
respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or
ocular herpes simplex.
Transferring Patients From Systemic Corticosteroid
Particular care is needed for patients who have been
transferred from systemically active corticosteroids to inhaled corticosteroids
because deaths due to adrenal insufficiency have occurred in patients with
asthma 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
hypothalamic-pituitary-adrenal (HPA) function.
Patients who have been previously maintained on 20 mg or
more 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 FLOVENT HFA may control 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 warning card indicating that they may need supplementary
systemic corticosteroids during periods of stress or a severe asthma attack.
Patients requiring oral corticosteroids should be weaned
slowly from systemic corticosteroid use after transferring to FLOVENT HFA.
Prednisone reduction can be accomplished by reducing the daily prednisone dose
by 2.5 mg on a weekly basis during therapy with FLOVENT HFA. Lung function
(mean forced expiratory volume in 1 second [FEV1] or morning peak
expiratory flow [AM PEF]), beta-agonist use, and asthma symptoms should be
carefully monitored during withdrawal of oral corticosteroids. In addition,
patients should be observed for signs and symptoms of adrenal insufficiency
such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.
Transfer of patients from systemic corticosteroid therapy
to FLOVENT HFA may unmask allergic conditions previously suppressed by the
systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema,
arthritis, eosinophilic conditions).
During withdrawal from oral corticosteroids, some
patients may experience symptoms of systemically active corticosteroid
withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance
or even improvement of respiratory function.
Hypercorticism And Adrenal Suppression
Fluticasone propionate will often help control asthma
symptoms with less suppression of HPA function than therapeutically equivalent
oral doses of prednisone. Since fluticasone propionate is absorbed into the
circulation and can be systemically active at higher doses, the beneficial
effects of FLOVENT HFA in minimizing HPA dysfunction may be expected only when
recommended dosages are not exceeded and individual patients are titrated to
the lowest effective dose. A relationship between plasma levels of fluticasone
propionate and inhibitory effects on stimulated cortisol production has been
shown after 4 weeks of treatment with fluticasone propionate inhalation
aerosol. Since individual sensitivity to effects on cortisol production exists,
physicians should consider this information when prescribing FLOVENT HFA.
Because of the possibility of significant systemic
absorption of inhaled corticosteroids in sensitive patients, patients treated
with FLOVENT HFA 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
It is possible that systemic corticosteroid effects such
as hypercorticism and adrenal suppression (including adrenal crisis) may appear
in a small number of patients who are sensitive to these effects. If such
effects occur, FLOVENT HFA should be reduced slowly, consistent with accepted
procedures for reducing systemic corticosteroids, and other treatments for
management of asthma symptoms should be considered.
Immediate Hypersensitivity Reactions
Immediate hypersensitivity reactions (e.g., urticaria,
angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur
after administration of FLOVENT HFA [see CONTRAINDICATIONS].
Reduction In Bone Mineral Density
Decreases in bone mineral density (BMD) have been
observed with long-term administration of products containing inhaled corticosteroids.
The clinical significance of small changes in BMD with regard to long-term
consequences such as fracture is unknown. Patients with major risk factors for decreased
bone mineral content, such as prolonged immobilization, family history of osteoporosis,
postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic
use of drugs that can reduce bone mass (e.g., anticonvulsants, oral
corticosteroids), should be monitored and treated with established standards of
A 2-year trial in 160 subjects (females aged 18 to 40
years, males 18 to 50) with asthma receiving chlorofluorocarbon (CFC)-propelled
fluticasone propionate inhalation aerosol 88 or 440 mcg twice daily
demonstrated no statistically significant changes in BMD at any time point (24,
52, 76, and 104 weeks of double-blind treatment) as assessed by dual-energy
x-ray absorptiometry at lumbar regions L1 through L4.
Effect On Growth
Orally inhaled corticosteroids may cause a reduction in
growth velocity when administered to pediatric patients. Monitor the growth of
pediatric patients receiving FLOVENT HFA routinely (e.g., via stadiometry). To
minimize the systemic effects of orally inhaled corticosteroids, including
FLOVENT HFA, titrate each patient's dosage to the lowest dosage that
effectively controls his/her symptoms [see DOSAGE AND ADMINISTRATION, Use
in Specific Populations].
Glaucoma And Cataracts
Glaucoma, increased intraocular pressure, and cataracts
have been reported in patients following the long-term administration of
inhaled corticosteroids, including fluticasone propionate. Therefore, close monitoring
is warranted in patients with a change in vision or with a history of increased
intraocular pressure, glaucoma, and/or cataracts.
As with other inhaled medicines, bronchospasm may occur
with an immediate increase in wheezing after dosing. If bronchospasm occurs
following dosing with FLOVENT HFA, it should be treated immediately with an
inhaled, short-acting bronchodilator; FLOVENT HFA should be discontinued immediately;
and alternative therapy should be instituted.
Drug Interactions With Strong Cytochrome P450 3A4
The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors
(e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole,
nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with FLOVENT
HFA is not recommended because increased systemic corticosteroid adverse
effects may occur [see DRUG INTERACTIONS, CLINICAL PHARMACOLOGY].
Eosinophilic Conditions And Churg-Strauss Syndrome
In rare cases, patients on inhaled fluticasone propionate
may present with systemic eosinophilic conditions. Some of these patients have
clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition
that is often treated with systemic corticosteroid therapy. These events
usually, but not always, have been associated with the reduction and/or
withdrawal of oral corticosteroid therapy following the introduction of
fluticasone propionate. Cases of serious eosinophilic conditions have also been
reported with other inhaled corticosteroids in this clinical setting.
Physicians should be alert to eosinophilia, vasculitic rash, worsening
pulmonary symptoms, cardiac complications, and/or neuropathy presenting in
their patients. A causal relationship between fluticasone propionate and these underlying
conditions has not been established.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Patient Information and Instructions for Use).
Inform patients that localized infections with Candida
albicans occurred in the mouth and pharynx in some patients. If oropharyngeal
candidiasis develops, treat it with appropriate local or systemic (i.e., oral)
antifungal therapy while still continuing therapy with FLOVENT HFA, but at
times therapy with FLOVENT HFA may need to be temporarily interrupted under
close medical supervision. Advise patients to rinse the mouth with water
without swallowing after inhalation to help reduce the risk of thrush.
Status Asthmaticus And Acute Asthma Symptoms
Inform patients that FLOVENT HFA is not a bronchodilator
and is not intended for use as rescue medicine for acute asthma exacerbations.
Advise patients to treat acute asthma symptoms with an inhaled, short-acting
beta2-agonist such as albuterol. Instruct patients to contact their physicians
immediately if there is deterioration of their asthma.
Warn patients who are on immunosuppressant doses of
corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to
consult their physicians without delay. Inform patients of potential worsening
of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or
ocular herpes simplex.
Hypercorticism And Adrenal Suppression
Advise patients that FLOVENT HFA may cause systemic corticosteroid
effects of hypercorticism and adrenal suppression. Additionally, inform
patients that deaths due to adrenal insufficiency have occurred during and
after transfer from systemic corticosteroids. Patients should taper slowly from
systemic corticosteroids if transferring to FLOVENT HFA.
Immediate Hypersensitivity Reactions
Advise patients that immediate hypersensitivity reactions
(e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including
anaphylaxis, may occur after administration of FLOVENT HFA. Patients should
discontinue FLOVENT HFA if such reactions occur.
Reduction in Bone Mineral Density: Advise patients who
are at an increased risk for decreased BMD that the use of corticosteroids may
pose an additional risk.
Reduced Growth Velocity
Inform patients that orally inhaled corticosteroids,
including FLOVENT HFA, may cause a reduction in growth velocity when
administered to pediatric patients. Physicians should closely follow the growth
of children and adolescents taking corticosteroids by any route.
Inform patients that long-term use of inhaled corticosteroids
may increase the risk of some eye problems (cataracts or glaucoma); consider
regular eye examinations.
Use Daily For Best Effect
Patients should use Flovent HFA at regular intervals as
directed. Individual patients will experience a variable time to onset and
degree of symptom relief and the full benefit may not be achieved until
treatment has been administered for 1 to 2 weeks or longer. Patients should not
increase the prescribed dosage but should contact their physicians if symptoms
do not improve or if the condition worsens. Instruct patients not to stop use
of FLOVENT HFA abruptly. Patients should contact their physicians immediately
if they discontinue use of FLOVENT HFA.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Fluticasone propionate demonstrated no tumorigenic
potential in mice at oral doses up to 1,000 mcg/kg (approximately 2 and 10
times the MRHDID for adults and children aged 4 to 11 years, respectively, on a
mg/m² basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg
(approximately 0.2 times and approximately equivalent to the MRHDID for adults
and children aged 4 to 11 years, respectively, on a mg/m² basis) for 104 weeks.
Fluticasone propionate did not induce gene mutation in
prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was
seen in cultured human peripheral lymphocytes in vitro or in the in vivo mouse
No evidence of impairment of fertility was observed in
male and female rats at subcutaneous doses up to 50 mcg/kg (approximately 0.2
times the MRHDID for adults on a mg/m² basis). Prostate weight was significantly
reduced at a subcutaneous dose of 50 mcg/kg.
Use In Specific Populations
Pregnancy Category C. There are no adequate and
well-controlled trials with FLOVENT HFA in pregnant women. Corticosteroids have
been shown to be teratogenic in laboratory animals when administered
systemically at relatively low dosage levels. Because animal reproduction studies
are not always predictive of human response, FLOVENT HFA should be used during
pregnancy only if the potential benefit justifies the potential risk to the
fetus. Women should be advised to contact their physicians if they become
pregnant while taking FLOVENT HFA.
Mice and rats at fluticasone propionate doses
approximately 0.1 and 0.5 times, respectively, the maximum recommended human
daily inhalation dose (MRHDID) for adults (on a mg/m² basis at maternal subcutaneous
doses of 45 and 100 mcg/kg/day, respectively) showed fetal toxicity
characteristic of potent corticosteroid compounds, including embryonic growth
retardation, omphalocele, cleft palate, and retarded cranial ossification. No
teratogenicity was seen in rats at doses up to 0.3 times the MRHDID (on a mcg/m²
basis at maternal inhaled doses up to 68.7 mcg/kg/day).
In rabbits, fetal weight reduction and cleft palate were
observed at a fluticasone propionate dose approximately 0.04 times the MRHDID
for adults (on a mg/m² basis at a maternal subcutaneous dose of 4 mcg/kg/day).
However, no teratogenic effects were reported at fluticasone propionate doses
up to approximately 3 times the MRHDID for adults (on a mg/m² basis at a
maternal oral dose up to 300 mcg/kg/day). No fluticasone propionate was
detected in the plasma in this study, consistent with the established low
bioavailability following oral administration [see CLINICAL PHARMACOLOGY].
Fluticasone propionate crossed the placenta following
subcutaneous administration to mice and rats and oral administration to
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.
In addition, because there is a natural increase in corticosteroid production
during pregnancy, most women will require a lower exogenous corticosteroid dose
and many will not need corticosteroid treatment during pregnancy.
Hypoadrenalism may occur in infants born of mothers
receiving corticosteroids during pregnancy. Such infants should be carefully
It is not known whether fluticasone propionate is
excreted in human breast milk. However, other corticosteroids have been
detected in human milk. Subcutaneous administration to lactating rats of tritiated
fluticasone propionate at a dose approximately 0.05 times the MRHDID in adults
on a mg/m² basis resulted in measurable radioactivity in milk.
Since there are no data from controlled trials on the use
of FLOVENT HFA by nursing mothers, caution should be exercised when FLOVENT HFA
is administered to a nursing woman.
The safety and effectiveness of FLOVENT HFA in children
aged 4 years and older have been established [see ADVERSE REACTIONS, CLINICAL
PHARMACOLOGY, Clinical Studies].The safety and effectiveness of
FLOVENT HFA in children younger than 4 years have not been established. Use of
FLOVENT HFA in patients aged 4 to 11 years is supported by evidence from
adequate and wellcontrolled trials in adults and adolescents aged 12 years and
older, pharmacokinetic trials in patients aged 4 to 11 years, established
efficacy of fluticasone propionate formulated as FLOVENT® DISKUS® (fluticasone
propionate inhalation powder) and FLOVENT® ROTADISK® (fluticasone propionate
inhalation powder) in patients aged 4 to 11 years, and supportive findings with
FLOVENT HFA in a trial conducted in subjects aged 4 to 11 years.
Effects On Growth
Orally inhaled corticosteroids may cause a reduction in
growth velocity when administered to pediatric patients. A reduction of growth
velocity in children or teenagers may occur as a result of poorly controlled
asthma or from use of corticosteroids including inhaled corticosteroids. The
effects of long-term treatment of children and adolescents with inhaled
corticosteroids, including fluticasone propionate, on final adult height are
Controlled clinical trials have shown that inhaled
corticosteroids may cause a reduction in growth in pediatric patients. In these
trials, the mean reduction in growth velocity was approximately 1 cm/year (range:
0.3 to 1.8 cm/year) and appeared to depend upon dose and duration of exposure.
This effect was observed in the absence of laboratory evidence of HPA axis
suppression, suggesting that growth velocity is a more sensitive indicator of
systemic corticosteroid exposure in pediatric patients than some commonly used
tests of HPA axis function. The long-term effects of this reduction in growth velocity
associated with orally inhaled corticosteroids, including the impact on final
adult height, are unknown. The potential for “catch-up” growth following
discontinuation of treatment with orally inhaled corticosteroids has not been
adequately studied. The effects on growth velocity of treatment with orally inhaled
corticosteroids for over 1 year, including the impact on final adult height,
are unknown. The growth of children and adolescents receiving orally inhaled
corticosteroids, including FLOVENT HFA, should be monitored routinely (e.g.,
via stadiometry). The potential growth effects of prolonged treatment should be
weighed against the clinical benefits obtained and the risks associated with alternative
therapies. To minimize the systemic effects of orally inhaled corticosteroids,
including FLOVENT HFA, each patient should be titrated to the lowest dose that
effectively controls his/her symptoms.
Since a cross trial comparison in adult and adolescent
subjects (aged 12 years and older) indicated that systemic exposure of inhaled
fluticasone propionate from FLOVENT HFA would be higher than exposure from
FLOVENT ROTADISK, results from a trial to assess the potential growth effects
of FLOVENT ROTADISK in pediatric subjects (aged 4 to 11 years) are provided.
A 52-week placebo-controlled trial to assess the
potential growth effects of fluticasone propionate inhalation powder (FLOVENT
ROTADISK) at 50 and 100 mcg twice daily was conducted in the US in 325
prepubescent children (244 males and 81 females) aged 4 to 11 years. The mean
growth velocities at 52 weeks observed in the intent-to-treat population were
6.32 cm/year in the placebo group (n = 76), 6.07 cm/year in the 50-mcg group (n
= 98), and 5.66 cm/year in the 100-mcg group (n = 89). An imbalance in the
proportion of children entering puberty between groups and a higher dropout
rate in the placebo group due to poorly controlled asthma may be confounding
factors in interpreting these data. A separate subset analysis of children who
remained prepubertal during the trial revealed growth rates at 52 weeks of 6.10
cm/year in the placebo group (n = 57), 5.91 cm/year in the 50-mcg group (n =
74), and 5.67 cm/year in the 100-mcg group (n = 79). In children aged 8.5
years, the mean age of children in this trial, the range for expected growth
velocity is: boys – 3rd percentile = 3.8 cm/year, 50th percentile =
5.4 cm/year, and 97th percentile = 7.0 cm/year; girls – 3rd percentile = 4.2
cm/year, 50th percentile = 5.7 cm/year, and 97th percentile = 7.3
cm/year. The clinical relevance of these growth data is not certain.
Children Younger Than 4 Years
Pharmacokinetics: [see CLINICAL PHARMACOLOGY].
A 12-week, double-blind, placebo-controlled,
parallel-group trial was conducted in children with asthma aged 1 to younger
than 4 years. Twelve-hour overnight urinary cortisol excretion after a 12-week
treatment period with 88 mcg of FLOVENT HFA twice daily (n = 73) and with
placebo (n = 42) were calculated. The mean and median change from baseline in
urine cortisol over 12 hours were -0.7 and 0.0 mcg for FLOVENT HFA and 0.3 and
-0.2 mcg for placebo, respectively.
In a 1-way crossover trial in children aged 6 to younger
than 12 months with reactive airways disease (N = 21), serum cortisol was
measured over a 12-hour dosing period. Subjects received placebo treatment for
a 2-week period followed by a 4-week treatment period with 88 mcg of FLOVENT
HFA twice daily with an AeroChamber Plus® Valved Holding Chamber (VHC) with
mask. The geometric mean ratio of serum cortisol over 12 hours (AUC0-12H )
following FLOVENT HFA (n = 16) versus placebo (n = 18) was 0.95 (95% CI: 0.72,
Safety: FLOVENT HFA administered as 88 mcg twice
daily was evaluated for safety in 239 pediatric subjects aged 1 to younger than
4 years in a 12-week, double-blind, placebo-controlled trial. Treatments were
administered with an AeroChamber Plus VHC with mask. The following events
occurred with a frequency greater than 3% and more frequently in subjects
receiving FLOVENT HFA than in subjects receiving placebo, regardless of
causality assessment: pyrexia, nasopharyngitis, upper respiratory tract infection,
vomiting, otitis media, diarrhea, bronchitis, pharyngitis, and viral infection.
FLOVENT HFA administered as 88 mcg twice daily was
evaluated for safety in 23 pediatric subjects aged 6 to 12 months in an
open-label placebo-controlled trial. Treatments were administered with an AeroChamber
Plus VHC with mask for 2 weeks with placebo followed by 4 weeks with active
drug. There was no discernable difference in the types of adverse events
reported between subjects receiving placebo compared with the active drug.
In Vitro Testing of Dose Delivery with Holding
Chambers: In vitro dose characterization studies were performed to evaluate
the delivery of FLOVENT HFA via holding chambers with attached masks. The studies
were conducted with 2 different holding chambers (AeroChamber Plus VHC and
AeroChamber Z-STAT Plus™ VHC) with masks (small and medium size) at inspiratory
flow rates of 4.9, 8.0, and 12.0 L/min in combination with holding times of 0,
2, 5, and 10 seconds. The flow rates were selected to be representative of
inspiratory flow rates of children aged 6 to 12 months, 2 to 5 years, and over
5 years, respectively. The mean delivered dose of fluticasone propionate
through the holding chambers with masks was lower than the 44 mcg of
fluticasone propionate delivered directly from the actuator mouthpiece. The
results were similar through both holding chambers (see Table 3 for data for
the AeroChamber Plus VHC). The fine particle fraction (approximately 1 to 5
μm) across the flow rates used in these studies was 70% to 84% of the
delivered dose, consistent with the removal of the coarser fraction by the
holding chamber. In contrast, the fine particle fraction for FLOVENT HFA
delivered without a holding chamber typically represents 42% to 55% of the
delivered dose measured at the standard flow rate of 28.3 L/min. These data
suggest that, on a per kilogram basis, young children receive a comparable dose
of fluticasone propionate when delivered via a holding chamber and mask as adults
do without their use.
Table 3: In Vitro Medication Delivery through
AeroChamber Plus® Valved Holding Chamber with a Mask
||Flow Rate (L/min)
||Holding Time (seconds)
||Mean Medication Delivery through AeroChamber Plus VHC (mcg/actuation)
||Body Weight 50th Percentile (kg)a
||Medication Delivered per Actuation (mcg/kg)b
|6 to 12 Months
|2 to 5 Years
||0 4-0 6
|2 to 5 Years
||0 4-0 6
| > 5 Years
|aCenters for Disease Control growth charts,
developed by the National Center for Health Statistics in collaboration with
the National Center for Chronic Disease Prevention and Health Promotion (2000).
Ranges correspond to the average of the 50 percentile weight for boys and girls
at the ages indicated.
bA single inhalation of FLOVENT HFA in a 70-kg adult without use of
a valved holding chamber and mask delivers approximately 44 mcg, or 0.6 mcg/kg.
Of the total number of subjects treated with FLOVENT HFA
in US and non-US clinical trials, 173 were aged 65 years or older, 19 of which
were 75 years or older. No overall differences in safety or effectiveness were
observed between these subjects and younger subjects, and other reported
clinical experience has not identified differences in responses between the
elderly and younger subjects, but greater sensitivity of some older individuals
cannot be ruled out.
Formal pharmacokinetic studies using FLOVENT HFA have not
been conducted in patients with hepatic impairment. Since fluticasone
propionate is predominantly cleared by hepatic metabolism, impairment of liver
function may lead to accumulation of fluticasone propionate in plasma.
Therefore, patients with hepatic disease should be closely monitored.
Formal pharmacokinetic studies using FLOVENT HFA have not
been conducted in patients with renal impairment.