Included as part of the PRECAUTIONS section.
Local Nasal Effects
Epistaxis, Nasal Erosions And Ulcerations
In placebo-controlled clinical trials of 16 weeks
duration, epistaxis, nasal erosions, and nasal ulcerations were reported more
frequently in patients treated with XHANCE than those who received placebo [see
Nasal Septal Perforation
Nasal septal perforations have been reported in patients
following the intranasal application of XHANCE. In placebo-controlled clinical
trials of 16 weeks duration, nasal septal perforations were reported in 1
(0.3%) patient treated with XHANCE compared with none treated with placebo. The
patient had a prior history of nasal/sinus surgery. Three (0.3%) patients
treated with XHANCE in uncontrolled, open-label trials of 3 to 12 months
duration developed nasal septal perforations.
As with any long term topical treatment of the nasal
cavity, patients using XHANCE over several months or longer should be examined
periodically for possible changes in the nasal mucosa. If a septal perforation
is noted, discontinue XHANCE. Avoid spraying XHANCE directly on the septum.
In clinical trials with XHANCE, localized infections with
Candida albicans have been observed. Eight (0.9%) patients in uncontrolled,
open-label trials of 3 to 12 months duration developed Candida albicans infections
(nasal, pharyngeal, esophageal or intestinal). If such an infection develops,
it may require treatment with appropriate local therapy and discontinuation of
XHANCE. Patients using XHANCE should be examined periodically for evidence of Candida
infection in the nasal and oropharyngeal mucosa.
Impaired Wound Healing
Because of the inhibitory effect of corticosteroids on
wound healing, patients who have experienced recent nasal ulcerations, nasal
surgery, or nasal trauma should avoid using XHANCE until healing has occurred.
Glaucoma And Cataracts
Nasal and inhaled corticosteroids, including fluticasone
propionate, may result in the development of glaucoma and/or cataracts. In
placebo-controlled clinical trials of 16 weeks duration, cataracts were
reported in 4 (1.2%) patients treated with XHANCE, compared with 3 (1.9%)
patients treated with placebo. Among these patients, 2 patients treated with
XHANCE reported subcapsular cataracts compared with none treated with placebo. Eleven
patients (1.2%) in uncontrolled, open-label trials of 3 to 12 months duration
developed new or worsening cataracts, of which none were subcapsular.
Therefore, close monitoring is warranted in patients with a change in vision or
with a history of increased intraocular pressure (IOP), glaucoma, and/or
Hypersensitivity Reactions Including Anaphylaxis
XHANCE is contraindicated in patients with known hypersensitivity
to fluticasone propionate or any of the ingredients of XHANCE. Discontinue
XHANCE if such reactions (e.g., anaphylaxis, angioedema, urticaria, contact
dermatitis, rash, hypotension, and bronchospasm) occur [see CONTRAINDICATIONS
and ADVERSE REACTIONS].
Persons who are using drugs that suppress the immune
system are more susceptible to infections than healthy individuals and may
experience a worsening of existing infections. Chickenpox and measles, for
example, can have a more serious or even fatal course in susceptible adults
using corticosteroids. In such 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 disseminated 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.) Â If chickenpox develops, treatment with antiviral agents may be
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 [see ADVERSE REACTIONS].
Hypothalamic-Pituitary-Adrenal Axis Effects
Hypercorticism and adrenal suppression may occur when
intranasal corticosteroids, such as XHANCE, are used at higher than recommended
dosages or in susceptible individuals at recommended dosages. Since fluticasone
propionate is absorbed into the circulation and can be systemically active at
higher doses, recommended dosages of XHANCE should not be exceeded to avoid
hypothalamic-pituitary-adrenal (HPA) dysfunction. A relationship between plasma
levels of fluticasone propionate and inhibitory effects on stimulated cortisol production
has been shown after 4 weeks of pulmonary treatment with fluticasone propionate
inhalation aerosol. Since individual sensitivity to effects on cortisol
production exists, physicians should consider this information when prescribing
Patients treated with XHANCE should be observed carefully
for any evidence of systemic corticosteroid effects such as hypercorticism and
adrenal suppression (including adrenal crisis). If such effects occur, the
dosage of XHANCE should be reduced slowly, consistent with accepted procedures
for reducing systemic corticosteroids, and other treatments for management of
nasal symptoms should be considered. Particular care should be taken in
observing patients postoperatively or during periods of stress for evidence of
inadequate adrenal response.
The replacement of a systemic corticosteroid with a
topical corticosteroid can be accompanied by signs of adrenal insufficiency. In
addition, some patients may experience symptoms of corticosteroid withdrawal
(e.g., joint and/or muscular pain, lassitude, depression). After withdrawal
from systemic corticosteroids, a number of months are required for recovery of
HPA function. Patients previously treated for prolonged periods with systemic
corticosteroids and transferred to topical corticosteroids should be carefully
monitored for acute adrenal insufficiency in response to stress such as trauma,
surgery, infection (particularly gastroenteritis), or other conditions
associated with severe electrolyte loss. In patients who have asthma or other
clinical conditions requiring long-term systemic corticosteroid treatment,
rapid decreases in systemic corticosteroid dosages may cause a severe
exacerbation of their symptoms [see ADVERSE REACTIONS and CLINICAL
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, conivaptan,
lopinavir, voriconazole) with XHANCE is not recommended because increased
systemic corticosteroid adverse effects may occur [see DRUG INTERACTIONS
and CLINICAL PHARMACOLOGY].
Reduction In Bone Mineral Density
Decreases in bone mineral density (BMD) have been
observed with long-term oral inhalation of products containing corticosteroids
into the lungs. 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 care.
A 2-year trial in 160 subjects (females aged 18 to 40
years, males aged 18 to 50 years) 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
Intranasal corticosteroids may cause a reduction in
growth velocity when administered to pediatric patients. The safety and
efficacy of XHANCE has not been established in pediatric patients [see Use In
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (PATIENT INFORMATION and Instructions for Use).
Local Nasal Effects
Inform patients that treatment with XHANCE may lead to
adverse reactions, which include epistaxis, nasal erosions, and nasal
ulceration. Candida infection may also occur with treatment with XHANCE. In
addition, XHANCE has been associated with nasal septal perforation and impaired
wound healing. Patients who have experienced recent nasal ulcerations, nasal
surgery, or nasal trauma should not use XHANCE until healing has occurred [see WARNINGS
Glaucoma And Cataracts
Inform patients that glaucoma and cataracts are
associated with long-term use of nasal and orally inhaled corticosteroids,
including fluticasone propionate, and may increase the risk of some eye
problems. Consider regular eye exams. Advise patients to notify their
healthcare providers if a change in vision is noted while using XHANCE [see WARNINGS
Hypersensitivity Reactions, Including Anaphylaxis
Inform patients that hypersensitivity reactions,
including anaphylaxis, angioedema, urticaria, contact dermatitis, rash,
bronchospasm, and hypotension, may occur after administration of fluticasone.
If such reactions occur during use with XHANCE, patients should discontinue use
of the product [see WARNINGS AND PRECAUTIONS].
Warn patients who are on immunosuppressant doses of
corticosteroids to avoid exposure to chickenpox or measles, and if they are
exposed to consult their healthcare provider without delay. Inform patients of
potential worsening of existing tuberculosis; fungal, bacterial, viral, or
parasitic infections; or ocular herpes simplex [see WARNINGS AND PRECAUTIONS].
Hypercorticism And Adrenal Suppression
Advise patients that XHANCE 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 XHANCE [see WARNINGS AND
Reduction In Bone Mineral Density
Advise patients who are at an increased risk for decreased
bone mineral density that the use of corticosteroids may pose an additional
risk [see WARNINGS AND PRECAUTIONS].
Reduced Growth Velocity
The safety and efficacy of XHANCE use in pediatric
patients has not been established. Inform patients that corticosteroids
administered by oral inhalation into the lungs or intranasally may cause a
reduction in growth velocity when administered to pediatric patients [see WARNINGS
Use Twice Daily For Best Effect
Inform patients that they should use XHANCE on a regular
basis as directed. XHANCE, like other corticosteroids, does not have an
immediate effect on nasal polyps or symptoms. 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 up to 16 weeks or
longer. Maximum benefit may not be reached for a period of months. Patients
should not increase the prescribed dosage, but should contact their healthcare providers
if symptoms do not improve or if the condition worsens.
If a patient missed a dose, the patient should be advised
to take the dose as soon as they remember. The patient should not take more
than the recommended dose for the day.
Keep Spray Out Of Eyes And Mouth
Inform patients to avoid spraying XHANCE in their eyes
How To Use XHANCE
It is important for patients to understand how to
correctly administer XHANCE nasal spray using the exhalation delivery system.
Advise the patient to carefully read the patient Instructions for Use. Any
questions regarding use that the patient has should be directed to the
physician or pharmacist.
Advise the patient to shake before each use.
The patient should note the difference in appearance of
the cone-shaped, non-flexible nosepiece and the longer flexible mouthpiece.
The patient should be instructed to gently insert the
tapered tip of the cone-shaped nosepiece deeply into the nose in order to
gently expand the nasal passage and to create a tight seal between the
nosepiece and the nostril. A seal must be maintained as the patient blows into
the mouthpiece and actuates the spray pump.
To actuate the device, patients should be advised to push
the bottle up while continuing to blow forcefully into the mouthpiece. Pushing
the bottle up actuates the spray pump, releasing a metered dose of aerosolized medication
while simultaneously allowing a “burst” of exhaled breath to pass through the
device. This helps deliver the medication deep into the patient's nose.
Patients should be advised not to try to inhale (e.g.,
“sniff”) when blowing (exhaling) into the mouthpiece.
Patients should be advised not to block the other nostril
because the exhaled breath must pass around the back of the nasal septum and
out the other side of the nose.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Fluticasone propionate demonstrated no tumorigenic
potential in mice at oral doses up to 1000 mcg/kg (approximately 7 times the
MRHDID for adults on a mcg/m² basis) for 78 weeks or in rats at inhalation
doses up to 57 mcg/kg (approximately equivalent to the MRHDID for adults on a
mcg/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 micronucleus
Fertility and reproductive performance were unaffected in
male and female rats at subcutaneous doses up to 50 mcg/kg (approximately 0.7
times the MRHDID for adults on a mcg/m² basis).
Use In Specific Populations
Available data from published literature on the use of
inhaled or intranasal fluticasone propionate in pregnant women have not
reported a clear association with adverse developmental outcomes. In animals,
teratogenicity characteristic of corticosteroids, decreased fetal body weight,
and/or skeletal variations in rats, mice, and rabbits were observed with
subcutaneously administered maternal toxic doses of fluticasone propionate less
than the maximum recommended human daily inhaled dose (MRHDID) on a mcg/m² basis.
However, fluticasone propionate administered via inhalation to rats decreased
fetal body weight, but did not induce teratogenicity at a maternal toxic dose
less than the MRHDID on a mcg/m² basis (see Data). Experience with oral
corticosteroids suggests that rodents are more prone to teratogenic effects
from corticosteroids than humans.
The estimated background risk of major birth defects and
miscarriage for the indicated population is unknown. All pregnancies have a
background risk of birth defect, loss, or other adverse outcomes. In the U.S.
general population, the estimated risk of major birth defects and miscarriages
in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
In embryofetal development studies with pregnant rats and
mice dosed by the subcutaneous route throughout the period of organogenesis,
fluticasone propionate was teratogenic in both species. Omphalocele, decreased body
weight, and skeletal variations were observed in rat fetuses, in the presence
of maternal toxicity, at a dose approximately equivalent to the MRHDID (on a
mcg/m² basis with a maternal subcutaneous dose of 100 mcg/kg/day). The rat no
observed adverse effect level (NOAEL) was observed at approximately 0.4 times the
MRHDID (on a mcg/m² basis with a maternal subcutaneous dose of 30 mcg/kg/day).
Cleft palate and fetal skeletal variations were observed in mouse fetuses at a
dose approximately 0.3 times the MRHDID (on a mcg/m² basis with a maternal
subcutaneous dose of 45 mcg/kg/day). The mouse NOAEL was observed with a dose
approximately 0.1 times the MRHDID (on a mcg/m² basis with a maternal
subcutaneous dose of 15 mcg/kg/day).
In an embryofetal development study with pregnant rats
dosed by the inhalation route throughout the period of organogenesis,
fluticasone propionate produced decreased fetal body weights and skeletal
variations, in the presence of maternal toxicity, at a dose approximately 0.34
times the MRHDID (on a mcg/m² basis with a maternal inhalation dose of 25.7
mcg/kg/day); however, there was no evidence of teratogenicity. The NOAEL was
observed with a dose approximately 0.1 times the MRHDID (on a mcg/m² basis with
a maternal inhalation dose of 5.5 mcg/kg/day).
In an embryofetal development study in pregnant rabbits
that were dosed by the subcutaneous route throughout organogenesis, fluticasone
propionate produced reductions of fetal body weights, in the presence of
maternal toxicity, at doses approximately 0.02 times the MRHDID and higher (on
a mcg/m² basis with a maternal subcutaneous dose of 0.57 mcg/kg/day).
Teratogenicity was evident based upon a finding of cleft palate for 1 fetus at
a dose approximately 0.1 times the MRHDID (on a mcg/m² basis with a maternal
subcutaneous dose of 4 mcg/kg/day). The NOAEL was observed in rabbit fetuses
with a dose approximately 0.002 times the MRHDID (on a mcg/m² basis with a
maternal subcutaneous dose of 0.08 mcg/kg/day).
Fluticasone propionate crossed the placenta following
subcutaneous administration to mice and rats and oral administration to
In a pre- and post-natal development study in pregnant
rats dosed from late gestation through delivery and lactation (Gestation Day 17
to Postpartum Day 22), fluticasone propionate was not associated with decreases
in pup body weight, and had no effects on developmental landmarks, learning,
memory, reflexes, or fertility at doses up to 0.7 times the MRHDID (on a mcg/m²
basis with maternal subcutaneous doses up to 50 mcg/kg/day).
There are no available data on the presence of
fluticasone propionate in human milk, the effects on the breastfed child, or
the effects on milk production. Fluticasone propionate is present in rat milk (see
Data). Other corticosteroids have been detected in human milk. However,
fluticasone propionate concentrations in plasma after orally inhaled
therapeutic doses are low, and therefore, concentrations in human breast milk
are likely to be correspondingly low [see CLINICAL PHARMACOLOGY]. The
developmental and health benefits of breastfeeding should be considered along
with the mother's clinical need for XHANCE and any potential adverse effects on
the breastfed child from XHANCE or from the underlying maternal condition.
Subcutaneous administration of tritiated fluticasone
propionate at a dose in lactating rats approximately 0.1 times the MRHDID for
adults (on a mcg/m² basis) resulted in measurable levels in milk.
The safety and efficacy of XHANCE in pediatric patients
have not been established.
Effects On Growth
Controlled clinical trials have shown that intranasal
corticosteroids may cause a reduction in growth velocity when administered to
pediatric patients. 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 intranasal corticosteroids,
including the impact on final adult height, are unknown. The potential for
“catch-up” growth following discontinuation of treatment with intranasal
corticosteroids has not been adequately studied. The growth of pediatric
patients receiving intranasal corticosteroids 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.
Controlled clinical trials have shown that
corticosteroids orally inhaled into the lungs 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. The effects on growth velocity of treatment
with corticosteroids orally inhaled into the lungs for over 1 year, including
the impact on final adult height, are unknown. The growth of children and
adolescents receiving corticosteroids should be monitored routinely (e.g., via
stadiometry) [see WARNINGS AND PRECAUTIONS].
Clinical trials of XHANCE did not include sufficient
numbers of subjects aged 65 years and older to determine whether they responded
differently than younger subjects. Other reported clinical experience with
fluticasone administered intranasal or orally inhaled has not identified
differences in responses between the elderly and younger patients, but greater
sensitivity of some older individuals cannot be ruled out.
Formal pharmacokinetic trials using XHANCE have not been
conducted in subjects 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 trials using XHANCE have not been
conducted in subjects with renal impairment.