Source: FDA, National Drug Code (US) Revision Year: 2020
NASONEX is a corticosteroid demonstrating potent 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.
In two clinical studies utilizing nasal antigen challenge, NASONEX 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 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 (e.g., eosinophils, lymphocytes, monocytes, neutrophils, and plasma cells).
Adrenal Function in Adults: Four clinical pharmacology studies have been conducted in humans to assess the effect of NASONEX at various doses on adrenal function. In one study, daily doses of 200 and 400 mcg of NASONEX and 10 mg of prednisone were compared to placebo in 64 patients (22 to 44 years of age) 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 at both the 200- and 400-mcg 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 (400 and 1600 mcg/day), prednisone (10 mg/day), and placebo, administered for 29 days in 48 male volunteers (21 to 40 years of age). 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 in adrenal function were observed with NASONEX compared to placebo.
A third study evaluated single, rising doses of NASONEX (1000, 2000, and 4000 mcg/day), orally administered mometasone furoate (2000, 4000, and 8000 mcg/day), orally administered dexamethasone (200, 400, and 800 mcg/day), and placebo (administered at the end of each series of doses) in 24 male volunteers (22 to 39 years of age). 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 or oral mometasone, as compared with placebo treatment. Conversely, nearly all volunteers treated with the three doses of dexamethasone demonstrated abnormal 8 AM cortisol levels (defined as a cortisol level <10 mcg/dL), reduced 24-hour plasma AUC values, and decreased 24-hour urinary free cortisol levels, as compared to placebo treatment.
In a fourth study, adrenal function was assessed in 213 patients (18 to 81 years of age) with nasal polyps before and after 4 months of treatment with either NASONEX (200 mcg once or twice daily) or placebo by measuring 24-hour urinary free cortisol levels. NASONEX at both doses (200 and 400 mcg/day), was not associated with statistically significant decreases in the 24-hour urinary free cortisol levels compared to placebo.
Three clinical pharmacology studies have been conducted in pediatric patients to assess the effect of mometasone furoate nasal spray on the adrenal function at daily doses of 50, 100, and 200 mcg vs. placebo. In one study, adrenal function before and after 7 consecutive days of treatment was assessed in 48 pediatric patients with allergic rhinitis (ages 6 to 11 years) by measuring morning plasma cortisol and 24-hour urinary free cortisol levels. Mometasone furoate nasal spray, at all three doses, was not associated with a statistically significant decrease in mean plasma cortisol levels or a statistically significant decrease in the 24-hour urinary free cortisol levels compared to placebo. In the second study, adrenal function before and after 14 consecutive days of treatment was assessed in 48 pediatric patients (ages 3 to 5 years) with allergic rhinitis by measuring plasma cortisol levels following a 30-minute Cortrosyn infusion. Mometasone furoate nasal spray, 50 mcg, at all three doses (50, 100, and 200 mcg/day), was not associated with a statistically significant decrease in mean plasma cortisol levels post-Cortrosyn infusion compared to placebo. All patients had a normal response to Cortrosyn. In the third study, adrenal function before and after up to 42 consecutive days of once-daily treatment was assessed in 52 patients with allergic rhinitis (ages 2 to 5 years), 28 of whom received mometasone furoate nasal spray, 50 mcg per nostril (total daily dose 100 mcg), by measuring morning plasma cortisol and 24-hour urinary free cortisol levels. Mometasone furoate nasal spray was not associated with a statistically significant decrease in mean plasma cortisol levels or a statistically significant decrease in the 24-hour urinary free cortisol levels compared to placebo.
Mometasone furoate monohydrate administered as a nasal spray suspension has very low bioavailability (<1%) in plasma using a sensitive assay with a lower quantitation limit (LOQ) of 0.25 pcg/mL.
The in vitro protein binding for mometasone furoate was reported to be 98% to 99% in concentration range of 5 to 500 ng/mL.
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.
Studies have shown that any portion of a mometasone furoate dose which is swallowed and absorbed undergoes extensive metabolism to multiple metabolites. There are no major metabolites detectable in plasma. Upon in vitro incubation, one of the minor metabolites formed is 6ß-hydroxy-mometasone furoate. In human liver microsomes, the formation of the metabolite is regulated by cytochrome P-450 3A4 (CYP3A4).
Patients with Hepatic Impairment: Administration of a single inhaled dose of 400 mcg mometasone furoate to subjects with mild (n=4), moderate (n=4), and severe (n=4) hepatic impairment resulted in only 1 or 2 subjects in each group having detectable peak plasma concentrations of mometasone furoate (ranging from 50 to 105 pcg/mL). The observed peak plasma concentrations appear to increase with severity of hepatic impairment, however, the numbers of detectable levels were few.
Patients with Renal Impairment: The effects of renal impairment on mometasone furoate pharmacokinetics have not been adequately investigated.
Pediatric Patients: Mometasone furoate pharmacokinetics have not been investigated in the pediatric population [see Use in Specific Populations (8.4)].
Male and Female Patients: The effects of gender on mometasone furoate pharmacokinetics have not been adequately investigated.
Racial or Ethnic Groups: The effects of race on mometasone furoate pharmacokinetics have not been adequately investigated.
Inhibitors of Cytochrome P450 3A4: In a drug interaction study, an inhaled dose of mometasone furoate 400 mcg was given to 24 healthy subjects twice daily for 9 days and ketoconazole 200 mg (as well as placebo) were given twice daily concomitantly on Days 4 to 9. Mometasone furoate plasma concentrations were <150 pcg/mL on Day 3 prior to coadministration of ketoconazole or placebo. Following concomitant administration of ketoconazole, 4 out of 12 subjects in the ketoconazole treatment group (n=12) had peak plasma concentrations of mometasone furoate >200 pcg/mL on Day 9 (211-324 pcg/mL).
In a 2-year carcinogenicity study in Sprague Dawley rats, mometasone furoate demonstrated no statistically significant increase in the incidence of tumors at inhalation doses up to 67 mcg/kg (approximately 1 and 2 times the maximum recommended daily nasal dose [MRDID] in adults [400 mcg] and children [100 mcg], respectively, on a mcg/m2 basis). In a 19-month carcinogenicity study in Swiss CD-1 mice, mometasone furoate demonstrated no statistically significant increase in the incidence of tumors at inhalation doses up to 160 mcg/kg (approximately 2 times the MRDID in adults and children, respectively, on a mcg/m2 basis).
Mometasone furoate increased chromosomal aberrations in an in vitro Chinese hamster ovary-cell assay, but did not increase chromosomal aberrations in an in vitro Chinese hamster lung cell assay. Mometasone furoate was not mutagenic in the Ames test or mouse-lymphoma assay, and was not clastogenic in an in vivo mouse micronucleus assay and a rat bone marrow chromosomal aberration assay or a mouse male germ-cell chromosomal aberration assay. Mometasone furoate also did not induce unscheduled DNA synthesis in vivo in rat hepatocytes.
In reproductive studies in rats, impairment of fertility was not produced by subcutaneous doses up to 15 mcg/kg (less than the MRDID in adults on a mcg/m2 basis).
In mice, mometasone furoate caused cleft palate at subcutaneous doses of 60 mcg/kg and above (less than the MRDID in adults on a mcg/m2 basis). Fetal survival was reduced at 180 mcg/kg (approximately 2 times the MRDID in adults on a mcg/m2 basis). No toxicity was observed at 20 mcg/kg (less than the MRDID in adults on a mcg/m2 basis).
In rats, mometasone furoate produced umbilical hernia at topical dermal doses of 600 mcg/kg and above (approximately 10 times the MRDID in adults on a mcg/m2 basis). A dose of 300 mcg/kg (approximately 6 times the MRDID in adults on a mcg/m2 basis) produced delays in ossification, but no malformations. In rabbits, mometasone furoate caused multiple malformations (e.g., flexed front paws, gallbladder agenesis, umbilical hernia, hydrocephaly) at topical dermal doses of 150 mcg/kg and above (approximately 6 times the MRDID in adults on a mcg/m2 basis). In an oral study, mometasone furoate increased resorptions and caused cleft palate and/or head malformations (hydrocephaly or domed head) at 700 mcg/kg (approximately 30 times the MRDID in adults on a mcg/m2 basis). At 2800 mcg/kg (approximately 110 times the MRDID in adults on a mcg/m2 basis), most litters were aborted or resorbed. No toxicity was observed at 140 mcg/kg (approximately 6 times the MRDID in adults on a mcg/m2 basis).
When rats received subcutaneous doses of mometasone furoate throughout pregnancy or during the later stages of pregnancy, 15 mcg/kg (less than the MRDID in adults on a mcg/m2 basis) caused prolonged and difficult labor and reduced the number of live births, birth weight, and early pup survival. Similar effects were not observed at 7.5 mcg/kg (less than the MRDID in adults on a mcg/m2 basis).
The efficacy and safety of NASONEX 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 (ages 17 to 85 years) and adolescents (ages 12 to 16 years). Of the total number of patients, there were 1757 males and 1453 females, including a total of 283 adolescents (182 boys and 101 girls) with seasonal allergic or perennial allergic rhinitis. Patients were treated with NASONEX at doses ranging from 50 to 800 mcg/day. The majority of patients were treated with 200 mcg/day. The allergic rhinitis trials evaluated the total nasal symptom scores that included stuffiness, rhinorrhea, itching, and sneezing. Patients treated with NASONEX 200 mcg/day had a statistically significant decrease in total nasal symptom scores compared to placebo-treated patients. No additional benefit was observed for mometasone furoate doses greater than 200 mcg/day. A total of 350 patients have been treated with NASONEX for 1 year or longer.
In patients with seasonal allergic rhinitis, NASONEX demonstrated improvement in nasal symptoms (vs. placebo) within 11 hours after the first dose based on one single-dose, parallel-group study of patients in an outdoor “park” setting (park study) and one environmental exposure unit (EEU) study, and within 2 days in two randomized, double-blind, placebo-controlled, parallel-group seasonal allergic rhinitis studies. 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 given at a dose of 200 mcg/day, was evaluated in two clinical studies in 284 patients. These studies were designed such that patients received 4 weeks of prophylaxis with NASONEX prior to the anticipated onset of the pollen season; however, some patients received only 2 to 3 weeks of prophylaxis. Patients receiving 2 to 4 weeks of prophylaxis with NASONEX demonstrated a statistically significantly smaller mean increase in total nasal symptom scores with onset of the pollen season as compared to placebo patients.
The efficacy and safety of NASONEX in the treatment of seasonal allergic and perennial allergic rhinitis in pediatric patients (ages 3 to 11 years) have been evaluated in four controlled trials. This included approximately 990 pediatric patients ages 3 to 11 years (606 males and 384 females) with seasonal allergic or perennial allergic rhinitis treated with mometasone furoate nasal spray at doses ranging from 25 to 200 mcg/day. Pediatric patients treated with NASONEX (100 mcg total daily dose, 374 patients) had a significant decrease in total nasal symptom (nasal congestion, rhinorrhea, itching, and sneezing) scores, compared to placebo-treated patients. No additional benefit was observed for the 200-mcg mometasone furoate total daily dose in pediatric patients (ages 3 to 11 years). A total of 163 pediatric patients have been treated for 1 year.
Two studies were performed to evaluate the efficacy and safety of NASONEX in the treatment of nasal polyps. These studies involved 664 patients with nasal polyps, 441 of whom received NASONEX. These studies were randomized, double-blind, placebo-controlled, parallel-group, multicenter studies in patients 18 to 86 years of age with bilateral nasal polyps. Patients were randomized to receive NASONEX 200 mcg once daily, 200 mcg twice daily or placebo for a period of 4 months. The co-primary efficacy endpoints were 1) change from baseline in nasal congestion/obstruction averaged over the first month of treatment; and 2) change from baseline to last assessment in bilateral polyp grade during the entire 4 months of treatment as assessed by endoscopy. Efficacy was demonstrated in both studies at a dose of 200 mcg twice daily and in one study at a dose of 200 mcg once a day (see Table 2 below).
Table 2. Effect of NASONEX in Two Randomized, Placebo-Controlled Trials in Patients with Nasal Polyps:
| NASONEX 200 mcg qd | NASONEX 200 mcg bid | Placebo | P-value for NASONEX 200 mcg qd vs. placebo | P-value for NASONEX 200 mcg bid vs. placebo | |
|---|---|---|---|---|---|
| Study 1 | N=115 | N=122 | N=117 | ||
| Baseline bilateral polyp grade* | 4.21 | 4.27 | 4.25 | ||
| Mean change from baseline in bilateral polyps grade | -1.15 | -0.96 | -0.50 | <0.001 | 0.01 |
| Baseline nasal congestion† | 2.29 | 2.35 | 2.28 | ||
| Mean change from baseline in nasal congestion | -0.47 | -0.61 | -0.24 | 0.001 | <0.001 |
| Study 2 | N=102 | N=102 | N=106 | ||
| Baseline bilateral polyp grade* | 4.00 | 4.10 | 4.17 | ||
| Mean change from baseline in bilateral polyps grade | -0.78 | -0.96 | -0.62 | 0.33 | 0.04 |
| Baseline nasal congestion† | 2.23 | 2.20 | 2.18 | ||
| Mean change from baseline in nasal congestion | -0.42 | -0.66 | -0.23 | 0.01 | <0.001 |
* polyps in each nasal fossa were graded by the investigator based on endoscopic visualization, using a scale of 0-3 where 0=no polyps; 1=polyps in the middle meatus, not reaching below the inferior border of the middle turbinate; 2=polyps reaching below the inferior border of the middle turbinate but not the inferior border of the inferior turbinate; 3=polyps reaching to or below the border of the inferior turbinate, or polyps medial to the middle turbinate (score reflects sum of left and right nasal fossa grades).
† nasal congestion/obstruction was scored daily by the patient using a 0-3 categorical scale where 0=no symptoms, 1=mild symptoms, 2=moderate symptoms and 3=severe symptoms.
There were no clinically relevant differences in the effectiveness of NASONEX in the studies evaluating treatment of nasal polyps across subgroups of patients defined by gender, age, or race.
The efficacy and safety of NASONEX for nasal congestion associated with seasonal allergic rhinitis were evaluated in three randomized, placebo-controlled, double blind clinical trials of 15 days duration. The three trials included a total of 1008 patients 12 years of age and older with nasal congestion associated with seasonal allergic rhinitis, of whom 506 received NASONEX 200 mcg daily and 502 received placebo. Of the 1008 patients, the majority 784 (78 ) were Caucasians. The majority of the patients were between 18 to <65 years of age with a mean age of 38.8 years and were predominantly women (66). The primary efficacy endpoint was the change from baseline in average morning and evening reflective nasal congestion score over treatment day 1 to day 15. The key secondary efficacy endpoint was the change from baseline in average morning and evening reflective total nasal symptom score (TNSS=rhinorrhea [nasal discharge/runny nose or postnasal drip], nasal congestion/stuffiness, nasal itching, sneezing) averaged over treatment day 1 to 15. Two out of three studies demonstrated that treatment with NASONEX significantly reduced the nasal congestion symptom score and the TNSS compared to placebo in patients 12 years of age and older with seasonal allergic rhinitis (see Tables 3 and 4 below).
Table 3. Effect of NASONEX in Two Randomized, Placebo-Controlled Trials on Nasal Congestion in Patients with Seasonal Allergic Rhinitis:
| Treatment (Patient Number) | Baseline* LS Mean† | Change from Baseline LS Mean† | Difference from Placebo LS Mean† | P-value for NASONEX 200 mcg qd vs. placebo |
|---|---|---|---|---|
| Study 1 | ||||
| NASONEX 200 mcg qd (N=176) | 2.63 | -0.64 | -0.15 | 0.006 |
| Placebo (N=175) | 2.62 | -0.49 | ||
| Study 2 | ||||
| NASONEX 200 mcg qd (N=168) | 2.62 | -0.71 | -0.31 | <0.001 |
| Placebo (N=164) | 2.60 | -0.40 | ||
* nasal congestion/obstruction was scored daily by the patient using a 0-3 categorical scale where 0=no symptoms, 1=mild symptoms, 2=moderate symptoms and 3=severe symptoms.
† LS Mean and p-value was from an ANCOVA model with treatment, baseline value, and center effects.
Table 4. Effect of NASONEX on TNSS in Two Randomized, Placebo-Controlled Trials in Patients with Seasonal Allergic Rhinitis:
| Treatment (Patient Number) | Baseline* LS Mean† | Change from Baseline LS Mean† | Difference from Placebo LS Mean† | P-value for NASONEX 200 mcg qd vs. placebo |
|---|---|---|---|---|
| Study 1 | ||||
| NASONEX 200 mcg qd (N=176) | 9.60 | -2.68 | -0.83 | <0.001 |
| Placebo (N=175) | 9.66 | -1.85 | ||
| Study 2 | ||||
| NASONEX 200 mcg qd (N=168) | 9.39 | -3.00 | -1.27 | <0.001 |
| Placebo (N=164) | 9.50 | -1.73 | ||
* TNSS was the sum of four individual symptom scores: rhinorrhea, nasal congestion/stuffiness, nasal itching and sneezing. Each symptom was to be rated on a scale of 0=none, 1=mild, 2=moderate, 3=severe.
† LS Mean and p-value was from an ANCOVA model with treatment, baseline value, and center effects.
Based on results in other studies with NASONEX in pediatric patients, effects on nasal congestion associated with seasonal allergic rhinitis in patients below 12 years of age is similar to those seen in adults and adolescents [see Clinical Studies (14.2)].
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