A1,
A2,
B,
C1,
C2,
D,
E,
F,
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I-K,
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P1,
P2,
Q-R,
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Elocon Pharmacology, Pharmacokinetics, Studies, Metabolism - Mometasone Furoate (nasal spray)
Elocon Pharmacology, Pharmacokinetics, Studies, Metabolism - Mometasone Furoate (nasal spray)
CLINICAL PHARMACOLOGY
NASONEX Nasal Spray, 50 µg is a corticosteroid
demonstrating anti- inflammatory properties. The precise mechanism
of corticosteroid
action on allergic
rhinitis is not known.
Corticosteroids have been shown to have a wide range
of effects on multiple
cell types (e.g., mast
cells, eosinophils, neutrophils, macrophages, and lymphocytes) and
mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines)
involved in inflammation.
Mometasone furoate demonstrated no
mineralocorticoid,
androgenic, antiandrogenic, or estrogenic
activity in preclinical
studies. After administration
of a single intranasal
dose of mometasone furoate
to adult male
rats, the highest drug
levels were seen in the esophagus, trachea, nasal
passage, and mouth.
In two clinical studies
utilizing nasal antigen
challenge, NASONEX Nasal Spray, 50 µg decreased some markers
of the early- and late- phase allergic response. These observations
included decreases (vs placebo) in histamine and eosinophil
cationic protein levels,
and reductions (vs. baseline) in eosinophils, neutrophils, and epithelial
cell adhesion
proteins. The clinical significance of these findings is not known.
The effect of NASONEX
Nasal Spray, 50 µg on nasal
mucosa following 12 months
of treatment was examined
in 46 patients with allergic
rhinitis. There was no evidence
of atrophy and there
was a marked reduction
in intraepithelial eosinophilia and inflammatory
cell infiltration
(eg, eosinophils, lymphocytes, monocytes, neutrophils, and plasma
cells).
Pharmacokinetics
Absorption: Mometasone furoate monohydrate administered
as a nasal spray
is virtually undetectable in plasma
despite the use of a sensitive
assay with a lower quantitation
limit (LOQ) of 50 pcg/mL.
Metabolism: Studies have shown that any portion of
a mometasone furoate dose
which is swallowed and absorbed under-goes extensive metabolism
to multiple metabolites.
Excretion: Following intravenous
administration, the effective plasma elimination
half-life of mometasone
furoate is 5.8 hours. Any absorbed drug is excreted as metabolites
mostly via the bile, and
to a limited extent, into the urine.
Special Populations: The effects of renal
impairment, hepatic impairment,
age, or gender on mometasone
furoate pharmacokinetics have not been adequately investigated.
Pharmacodynamics
Three clinical pharmacology
studies have been conducted in humans to assess the effect
of NASONEX Nasal Spray, 50 µg at various doses on adrenal
function. In one study, daily
doses of 200 and 400 µg of NASONEX Nasal Spray, 50 µg
and 10 mg of prednisone
were compared to placebo
in 64 patients with allergic
rhinitis. Adrenal function
before and after 36 consecutive days of treatment
was assessed by measuring plasma cortisol levels following a 6-hour
Cortrosyn (ACTH) infusion
and by measuring 24-hour urinary-free cortisol
levels. NASONEX Nasal Spray, 50 µg, at both the 200 and 400
µg dose, was not associated with a statistically significant
decrease in mean plasma
cortisol levels post-Cortrosyn
infusion or a statistically significant
decrease in the 24-hour urinary-free cortisol levels compared to
placebo. A statistically significant
decrease in the mean plasma
cortisol levels post-Cortrosyn
infusion and 24-hour
urinary-free cortisol levels was detected in the prednisone
treatment group
compared to placebo.
A second study assessed adrenal
response to NASONEX
Nasal Spray, 50 µg (400 and 1600 µg/day), prednisone
(10 mg/day), and placebo, administered for 29 days in 48 male
volunteers. The 24-hour plasma
cortisol area under the curve
(AUC0-24), during and after an 8-hour Cortrosyn infusion
and 24-hour urinary-free cortisol
levels were determined at baseline and after 29 days of treatment.
No statistically significant
differences of adrenal
function were observed
with NASONEX Nasal Spray, 50 µg compared to placebo.
A third study evaluated single, rising doses of NASONEX Nasal Spray,
50 µg (1000, 2000, and 4000 µg/day), orally administered
mometasone furoate (2000, 4000, and 8000 µg/day), orally administered
dexamethasone (200, 400, and 800 µg/day), and placebo
(administered at the end of each series
of doses) in 24 male volunteers.
Dose administrations were separated by at least 72 hours. Determination
of serial plasma
cortisol levels at 8 AM and for the 24-hour period
following each treatment
were used to calculate the plasma
cortisol area
under the curve (AUC0-24).
In addition, 24-hour urinary-free cortisol
levels were collected prior to initial
treatment administration
and during the period
immediately following each dose. No
statistically significant
decreases in the plasma
cortisol AUC, 8 AM cortisol
levels, or 24-hour urinary-free cortisol
levels were observed in volunteers treated with either NASONEX Nasal
Spray, 50 µg or oral
mometasone, as compared with placebo
treatment. Conversely, nearly all volunteers treated with the 3
doses of dexamethasone
demonstrated abnormal 8 AM cortisol
levels (defined as a cortisol
level <10 µg/dL), reduced 24-hour plasma
AUC values, and decreased
24-hour urinary-free cortisol levels, as compared to placebo
treatment.
Clinical Studies
The efficacy and safety
of NASONEX Nasal Spray, 50 µg in the prophylaxis and treatment
of seasonal allergic
rhinitis and the treatment
of perennial allergic rhinitis
have been evaluated in 18 controlled trials, and one uncontrolled
clinical trial, in
approximately 3000 adults (age 17 to 85) and adolescents (age 12
to 16). This included 1757 males and 1453 females, including a total
of 283 adolescents (182 boys and 101 girls) with seasonal allergic
or perennial allergic
rhinitis, treated with
NASONEX Nasal Spray, 50 µg at doses ranging from 50 to 800
µg/day. The majority of patients were treated with 200 µg/day.
These trials evaluated the total nasal
symptom scores that
included stuffiness, rhinorrhea,
itching, and sneezing. Patients treated with NASONEX Nasal Spray,
50 µg, 200 µg/day had a significant
decrease in total nasal
symptom scores compared
to placebo-treated patients. No
additional benefit was
observed for mometasone furoate doses greater than 200 µg/day.
A total of 350 patients have been treated with NASONEX Nasal Spray,
50 µg for 1 year or longer.
In patients with seasonal allergic
rhinitis, NASONEX Nasal
Spray, 50 µg demonstrated improvement in nasal
symptoms (vs. placebo) within 2 days after the first dose. Maximum
benefit is usually achieved
within 1 to 2 weeks after initiation of dosing.
Prophylaxis of seasonal allergic
rhinitis for patients
12 years of age and older with NASONEX Nasal Spray, 50 µg,
given at a dose of 200
µg/day, was evaluated in two clinical
studies in 284 patients. These studies were designed such
that patients received 4 weeks of prophylaxis with NASONEX Nasal
Spray, 50 µg prior to the anticipated onset of the pollen
season, how- ever, some patients received only 2 to 3 weeks of prophylaxis.
Patients receiving 2 to 4 weeks of prophylaxis
with NASONEX Nasal Spray, 50 µg demonstrated a statistically
significantly smaller mean increase in total nasal
symptom scores with
onset of the pollen season
as compared to placebo
patients.
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