ENT - September 2020 - 495

Drug Interactions with Strong Cytochrome P450 3A4
Inhibitors: 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.
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.
ADVERSE REACTIONS:
Clinical Trials Experience: Because clinical trials are conducted
under widely varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared with rates in the
clinical trials of another drug and may not reflect the rates observed in
practice. The safety data described below are based on two placebocontrolled clinical trials evaluating doses of a fluticasone propionate
exhalation delivery system from 93 mcg twice daily to 372 mcg twice
daily. Both trials were 16 weeks in duration with an additional 8-week
open-label extension. The trials included a total of 643 adult subjects
with bilateral nasal polyps and associated moderate or severe nasal
congestion, of which 161 received 93 mcg twice daily, 160 received
186 mcg twice daily, 161 received 372 mcg twice daily, and 161
received placebo. The overall pooled safety data included 296 (46.0%)
Female, 347 (54.0%) Male, 584 (90.8%) White, 39 (6.1%) Black, 9
(1.4%) Asian, and 11 (1.7%) subjects classified as Other. Of these
patients, 45 (7%) were 65 years of age or older. All adverse reactions
with an incidence of ≥3% in the XHANCE 186 mcg (n=160) and 372 mcg
(n=161) twice daily subjects, and more common than placebo (n=161)
were as follows (% Placebo, % XHANCE 186 mcg, and % XHANCE 372
mcg): Epistaxis (2.5%, 11.9%, 9.9%), Nasopharyngitis (5.0%, 1.9%,
7.5%), Nasal septal erosion and ulceration (1.9%, 6.9%, 7.5%), Nasal
congestion (3.7%, 4.4%, 5.6%), Acute sinusitis (3.7%, 4.4%, 5.0%),
Headache (3.1%, 5.0%, 3.7%), Pharyngitis (1.2%, 1.3%, 3.1%), Nasal
mucosal erosion and ulceration (1.3%, 3.8%, 2.5%), Nasal mucosal
erythema (3.7%, 5.6%, 5.0%), and Nasal septal erythema (1.9%, 3.8%,
4.3%). Other adverse reactions with XHANCE observed with an incidence
<3% but ≥1% and more common than placebo included: nasal dryness,
sinusitis, oropharyngeal pain, toothache, intraocular pressure increase,
dizziness, abdominal discomfort, and weight increase. 5.0% of subjects
treated with XHANCE 186 mcg twice daily and 1.2% of subjects treated
with 372 mcg twice daily discontinued from the clinical trials prior to
the open-label extension because of adverse reactions compared to
4.3% of subjects treated with placebo. There were no clinically relevant
differences in the incidence of adverse reactions based on gender. Clinical
trials did not include sufficient numbers of non-Caucasian patients or
patients aged 65 years and older to determine whether they respond
differently from Caucasian or younger patients, respectively. The adverse
reactions observed during uncontrolled, open-label trials of 3 to 12
months' duration in subjects with chronic sinusitis with and without nasal
polyps receiving XHANCE 372 mcg twice daily were similar to the adverse
reactions reported in clinical trials in patients with nasal polyps.

USE IN SPECIFIC POPULATIONS:
Pregnancy: 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. 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.
Lactation: 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. 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. 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.
Pediatric Use: The safety and efficacy of XHANCE in pediatric patients
have not been established.
Geriatric Use: 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.
Hepatic Impairment: 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.
Renal Impairment: Formal pharmacokinetic trials using XHANCE have not
been conducted in subjects with renal impairment.
OVERDOSAGE: Chronic overdosage may result in signs/symptoms
of hypercorticism. An intranasal dose of 2 mg (2.7 to 5.4 times the
recommended daily dose) of fluticasone propionate twice daily for 7 days
was administered to healthy human volunteers. Adverse events reported
with fluticasone propionate were similar to placebo, and no clinically
significant abnormalities in laboratory safety tests were observed.
Single oral doses up to 16 mg have been studied in human volunteers
with no acute toxic effects reported. Oral inhalation by healthy volunteers
of a single dose of 1.76 or 3.52 mg of fluticasone propionate was
well tolerated. Fluticasone propionate given by pulmonary inhalation
administration at dosages of 1.32 mg twice daily for 7 to 15 days to
healthy human volunteers was also well tolerated. Repeat oral doses
up to 80 mg daily for 10 days in volunteers and repeat oral doses up to
10 mg daily for 14 days in patients were well tolerated. Adverse reactions
were of mild or moderate severity, and incidences were similar in active
and placebo treatment groups.
To report SUSPECTED ADVERSE REACTIONS, contact OptiNose US, Inc. at
1-833-678-6673 or safety@optinose.com, or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
XHANCE and OptiNose are registered trademarks of OptiNose AS.
©2020 OptiNose US, Inc. All rights reserved.

http://www.fda.gov/medwatch

ENT - September 2020

Table of Contents for the Digital Edition of ENT - September 2020