Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism Of Action NASONEX Nasal Spray 50 mcg 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 Nasal Spray, 50 mcg 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 mcg 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). Pharmacodynamics Adrenal Function In Adults Four clinical pharmacology studies have been conducted in humans to assess the effect of NASONEX Nasal Spray, 50 mcg at various doses on adrenal function. In one study, daily doses of 200 and 400 mcg of NASONEX Nasal Spray, 50 mcg 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 Nasal Spray, 50 mcg, 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 Nasal Spray, 50 mcg (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 Nasal Spray, 50 mcg compared to placebo. A third study evaluated single, rising doses of NASONEX Nasal Spray, 50 mcg (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 Nasal Spray, 50 mcg 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 Nasal Spray, 50 mcg, (200 mcg once or twice daily) or placebo by measuring 24-hour urinary free cortisol levels. NASONEX Nasal Spray, 50 mcg, 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. Pharmacokinetics Absorption 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. Distribution The in vitro protein binding for mometasone furoate was reported to be 98% to 99% in concentration range of 5 to 500 ng/mL. Metabolism 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). Elimination 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. Specific Populations 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. Renal Impairment The effects of renal impairment on mometasone furoate pharmacokinetics have not been adequately investigated. Pediatric Mometasone furoate pharmacokinetics have not been investigated in the pediatric population [see Use In Specific Populations]. Gender The effects of gender on mometasone furoate pharmacokinetics have not been adequately investigated. Race The effects of race on mometasone furoate pharmacokinetics have not been adequately investigated. Drug-Drug Interactions 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). Animal Toxicology And/Or Pharmacology Reproduction Toxicology Studies 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). Clinical Studies Allergic Rhinitis In Adults And Adolescents The efficacy and safety of NASONEX Nasal Spray, 50 mcg 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 Nasal Spray 50 mcg 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 Nasal Spray 50 mcg, 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 Nasal Spray 50 mcg for 1 year or longer. In patients with seasonal allergic rhinitis, NASONEX Nasal Spray 50 mcg, demonstrated improvement in nasal symptoms (vs. placebo) within 11 hours after the first dose based on one single-dose, parallelgroup 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 Nasal Spray 50 mcg, 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 Nasal Spray 50 mcg 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 Nasal Spray 50 mcg demonstrated a statistically significantly smaller mean increase in total nasal symptom scores with onset of the pollen season as compared to placebo patients. Allergic Rhinitis In Pediatrics The efficacy and safety of NASONEX Nasal Spray 50 mcg 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 Nasal Spray 50 mcg (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. Nasal Polyps In Adults 18 Years Of Age And Older Two studies were performed to evaluate the efficacy and safety of NASONEX Nasal Spray in the treatment of nasal polyps. These studies involved 664 patients with nasal polyps, 441 of whom received NASONEX Nasal Spray. These studies were randomized, double-blind, placebo-controlled, parallelgroup, multicenter studies in patients 18 to 86 years of age with bilateral nasal polyps. Patients were randomized to receive NASONEX Nasal Spray 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 NASAL SPRAY IN TWO RANDOMIZED, PLACEBOCONTROLLED 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 Nasal Spray, 50 mcg, in the studies evaluating treatment of nasal polyps across subgroups of patients defined by gender, age, or race. Nasal Congestion Associated With Seasonal Allergic Rhinitis The efficacy and safety of NASONEX Nasal Spray 50 mcg 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 Nasal Spray 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 Nasal Spray 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 TABLE 3 and 4 below). TABLE 3: EFFECT OF NASONEX NASAL SPRAY IN TWO RANDOMIZED, PLACEBOCONTROLLED 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 NASAL SPRAY 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 Nasal Spray 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 Allergic Rhinitis In Pediatrics].

CLINICAL PHARMACOLOGY Mechanism of Action Like other topical corticosteroids, mometasone furoate has anti-inflammatory, antipruritic, and vasoconstrictive properties. The mechanism of the anti-inflammatory activity of the topical steroids, in general, is unclear. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. Pharmacodynamics Studies performed with ELOCON Cream indicate that it is in the medium range of potency as compared with other topical corticosteroids. In a study evaluating the effects of mometasone furoate cream on the HPA axis, 15 grams were applied twice daily for 7 days to six adult subjects with psoriasis or atopic dermatitis. The cream was applied without occlusion to at least 30% of the body surface. The results showed that the drug caused a slight lowering of adrenal corticosteroid secretion [see WARNINGS AND PRECAUTIONS]. Ninety-seven pediatric subjects ages 6 to 23 months with atopic dermatitis were enrolled in an open-label HPA axis safety study. ELOCON Cream was applied once daily for approximately 3 weeks over a mean body surface area of 41% (range 15%-94%). In approximately 16% of subjects who showed normal adrenal function by Cortrosyn test before starting treatment, adrenal suppression was observed at the end of treatment with ELOCON Cream. The criteria for suppression were: basal cortisol level of ≤ 5 mcg/dL, 30-minute post-stimulation level of ≤ 18 mcg/dL, or an increase of < 7 mcg/dL. Follow-up testing 2 to 4 weeks after stopping treatment, available for 5 of the subjects, demonstrated suppressed HPA axis function in one subject, using these same criteria [see Use in Specific Populations]. Pharmacokinetics The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle and the integrity of the epidermal barrier. Studies in humans indicate that approximately 0.4% of the applied dose of ELOCON Cream enters the circulation after 8 hours of contact on normal skin without occlusion. Inflammation and/or other disease processes in the skin may increase percutaneous absorption. Clinical Studies The safety and efficacy of the ELOCON Cream for the treatment of corticosteroid-responsive dermatoses were evaluated in two randomized, double-blind, vehicle-controlled clinical trials, one in psoriasis and one in atopic dermatitis. A total 366 subjects (12-81 years of age), of whom 177 received ELOCON Cream and 181 subjects received vehicle cream, were evaluated in these trials. ELOCON Cream or the vehicle cream were applied once daily for 21 days. The two trials showed ELOCON Cream is effective in the treatment of psoriasis and atopic dermatitis.

CLINICAL PHARMACOLOGY Mechanism Of Action Mometasone furoate is a corticosteroid demonstrating potent anti-inflammatory activity. The precise mechanism of corticosteroid action on asthma is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of inhibitory 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 and in the asthmatic response. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma. Mometasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor, which is approximately 12 times that of dexamethasone, 7 times that of triamcinolone acetonide, 5 times that of budesonide, and 1.5 times that of fluticasone. The clinical significance of these findings is unknown. Pharmacodynamics HPA Axis Effects The effects of inhaled mometasone furoate administered via ASMANEX HFA on adrenal function have not been directly evaluated. However, the effects of inhaled mometasone furoate, administered as part of a mometasone furoate/formoterol fumarate inhalation aerosol combination product, on adrenal function were evaluated in two clinical trials in patients with asthma. As no evidence of a pharmacokinetic drug interaction between mometasone furoate and formoterol was observed when the two drugs were administered in combination, the HPA axis effects from the combination product are applicable to ASMANEX HFA. For the mometasone furoate/formoterol fumarate combination product clinical program, HPA-axis function was assessed by 24-hour plasma cortisol AUC. Although both these trials have openlabel design and contain a small number of subjects per treatment arm, results from these trials taken together demonstrated suppression of 24-hour plasma cortisol AUC for the combination mometasone furoate/formoterol fumarate 200 mcg/5 mcg compared to placebo consistent with the known systemic effects of inhaled corticosteroid. In a 42-day, open-label, placebo- and active-controlled study, the mean change from baseline plasma cortisol AUC(0-24 hr) was 8%, 22% and 34% lower compared to placebo for the mometasone furoate/formoterol fumarate 100 mcg/5 mcg (n=13), mometasone furoate/formoterol fumarate 200 mcg/5 mcg (n=15) and fluticasone propionate/salmeterol xinafoate 230 mcg/21 mcg (n=16) treatment groups, respectively. In a 52-week, open-label safety study, the mean plasma cortisol AUC(0-24 hr) was 2.2%, 29.6%, 16.7%, and 32.2% lower from baseline for the mometasone furoate/formoterol fumarate 100 mcg/5 mcg (n=18), mometasone furoate/formoterol fumarate 200 mcg/5 mcg (n=20), fluticasone propionate/salmeterol xinafoate 125/25 mcg (n=8), and fluticasone propionate/salmeterol xinafoate 250/25 mcg (n=11) treatment groups, respectively. The potential effect of mometasone furoate via a dry powder inhaler (DPI) on the HPA axis was also assessed in a 29-day study. A total of 64 adult patients with mild to moderate asthma were randomized to one of 4 treatment groups: mometasone furoate DPI 440 mcg twice daily, mometasone furoate DPI 880 mcg twice daily, oral prednisone 10 mg once daily, or placebo. The 30-minute post- Cosyntropin stimulation serum cortisol concentration on Day 29 was 23.2 mcg/dL for the mometasone furoate DPI 440 mcg twice daily group and 20.8 mcg/dL for the mometasone furoate DPI 880 mcg twice daily group, compared to 14.5 mcg/dL for the oral prednisone 10 mg group and 25 mcg/dL for the placebo group. The difference between mometasone furoate DPI 880 mcg twice daily (twice the maximum recommended dose) and placebo was statistically significant. Pharmacokinetics As no evidence of a pharmacokinetic drug interaction between mometasone furoate and formoterol was observed when the two drugs were administered from a mometasone furoate/formoterol fumarate combination product, the pharmacokinetics information from the combination product is applicable to ASMANEX HFA. Absorption Healthy Subjects: Following oral inhalation of single doses of ASMANEX HFA, mometasone furoate was absorbed in healthy subjects with median Tmax values ranging from 0.50 to 2 hours. Following singledose administration of higher than recommended dose of ASMANEX HFA (4 inhalations of ASMANEX HFA 200 mcg) in healthy subjects, the arithmetic mean (CV%) Cmax and AUC(0-tf) values for mometasone furoate were 53 (102) pg/mL and 992 (80) pg•hr/mL, respectively. Studies using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of mometasone furoate is negligible ( < 1%). Asthma Patients: Following oral inhalation of single and multiple doses of the mometasone furoate/formoterol fumarate combination product, mometasone furoate was absorbed in asthma patients with median Tmax values ranging from 1 to 2 hours. Following single-dose administration of mometasone furoate/formoterol fumarate 400 mcg/10 mcg, the arithmetic mean (CV%) Cmax and AUC(0-12 hr) values for mometasone furoate were 20 (88) pg/mL and 170 (94) pg•hr/mL, respectively, while the corresponding estimates following twice daily dosing of mometasone furoate/formoterol fumarate 400 mcg/10 mcg at steady-state were 60 (36) pg/mL and 577 (40) pg•hr/mL. Distribution Based on the study employing a 1000 mcg inhaled dose of tritiated mometasone furoate inhalation powder in humans, no appreciable accumulation of mometasone furoate in the red blood cells was found. Following an intravenous 400 mcg dose of mometasone furoate, the plasma concentrations showed a biphasic decline, with a mean steady-state volume of distribution of 152 liters. The in vitro protein binding for mometasone furoate was reported to be 98% to 99% (in a concentration range of 5 to 500 ng/mL). Metabolism Studies have shown that mometasone furoate is primarily and extensively metabolized in the liver of all species investigated and undergoes extensive metabolism to multiple metabolites. In vitro studies have confirmed the primary role of human liver CYP3A4 in the metabolism of this compound; however, no major metabolites were identified. Human liver CYP3A4 metabolizes mometasone furoate to 6-beta hydroxy mometasone furoate. Excretion Following an intravenous dosing, the terminal half-life was reported to be about 5 hours. Following the inhaled dose of tritiated 1000 mcg mometasone furoate, the radioactivity is excreted mainly in the feces (a mean of 74%), and to a small extent in the urine (a mean of 8%) up to 7 days. No radioactivity was associated with unchanged mometasone furoate in the urine. Absorbed mometasone furoate is cleared from plasma at a rate of approximately 12.5 mL/min/kg, independent of dose. The effective t½ for mometasone furoate following inhalation with DULERA was 25 hours in healthy subjects and in patients with asthma. Special Populations Hepatic/Renal Impairment: There are no data regarding the specific use of ASMANEX HFA in patients with hepatic or renal impairment. A study evaluating the administration of a single inhaled dose of 400 mcg mometasone furoate by a dry powder inhaler 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 50-105 pg/mL). The observed peak plasma concentrations appear to increase with severity of hepatic impairment; however, the numbers of detectable levels were few. Gender and Race: Specific studies to examine the effects of gender and race on the pharmacokinetics of ASMANEX HFA have not been specifically studied. Geriatrics: The pharmacokinetics of ASMANEX HFA have not been specifically studied in the elderly population. Drug-Drug Interactions A single-dose crossover study was conducted to compare the pharmacokinetics of 4 inhalations of the following: mometasone furoate MDI, formoterol MDI, mometasone furoate/formoterol fumarate MDI combination product, and mometasone furoate MDI plus formoterol fumarate MDI administered concurrently. The results of the study indicated that there was no evidence of a pharmacokinetic interaction between mometasone furoate and formoterol. Inhibitors of Cytochrome P450 Enzymes: Ketoconazole: In a drug interaction study, an inhaled dose of mometasone furoate 400 mcg delivered by a dry powder inhaler 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 pg/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 pg/mL on Day 9 (211-324 pg/mL). Mometasone furoate plasma levels appeared to increase and plasma cortisol levels appeared to decrease upon concomitant administration of ketoconazole. Animal Toxicology And/Or Pharmacology Reproductive Toxicology Studies In mice, mometasone furoate caused cleft palate at subcutaneous doses of 60 mcg/kg and above (approximately one-third of the maximum recommended human dose MRHD on a mcg/m² basis). Fetal survival was reduced at 180 mcg/kg (approximately equal to the MRHD on a mcg/m² basis). No toxicity was observed at 20 mcg/kg (approximately one-tenth of the MRHD on a mcg/m² basis). In rats, mometasone furoate produced umbilical hernia at topical dermal doses of 600 mcg/kg and above (approximately 6 times the MRHD on a mcg/m² basis). A dose of 300 mcg/kg (approximately 3 times the MRHD on a mcg/m² basis) produced delays in ossification, but no malformations. When rats received subcutaneous doses of mometasone furoate throughout pregnancy or during the later stages of pregnancy, 15 mcg/kg (approximately 8 times the MRHD on an AUC 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 (approximately 4 times the MRHD on an AUC basis). 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 3 times the MRHD on a mcg/m² basis). In an oral study, mometasone furoate increased resorptions and caused cleft palate and/or head malformations (hydrocephaly and domed head) at 700 mcg/kg (less than the MRHD on an AUC basis). At 2800 mcg/kg (approximately 2 times the MRHD on an AUC basis) most litters were aborted or resorbed. No toxicity was observed at 140 mcg/kg (less than the MRHD on an AUC basis). Clinical Studies Asthma The safety and efficacy of ASMANEX HFA was demonstrated in two randomized, double-blind, placebo- or active-controlled multi-center clinical trials of 12 and 26 weeks' duration, conducted as part of a mometasone furoate/formoterol fumarate 100/5 mcg or 200/5 mcg combination product development program. A total of 1509 patients 12 years of age and older with persistent asthma (mean baseline FEV1 of 66% to 73% predicted) were evaluated. Trial 1: Clinical Trial with ASMANEX HFA 100 mcg This 26-week, placebo-controlled trial conducted as part of a mometasone furoate/formoterol fumarate combination product asthma program evaluated 781 patients 12 years of age and older. Of these patients, 192 patients received ASMANEX HFA 100 mcg and 196 patients received placebo, each administered as 2 inhalations twice daily by metered dose inhalation aerosols. All other maintenance therapies were discontinued. The study included a 2- to 3-week run-in period with ASMANEX HFA 100 mcg, 2 inhalations twice daily. Patients ranged from 12 to 76 years of age, 41% were male and 59% female, and 72% were Caucasian and 28% non-Caucasian. Patients had persistent asthma and were not well controlled on medium dose of inhaled corticosteroids prior to randomization. Mean FEV1 and mean percent predicted FEV1 were similar among all treatment groups (2.33 L, 73%). Thirteen (7%) patients receiving ASMANEX HFA 100 mcg and 46 (23%) patients receiving placebo discontinued the study early due to treatment failure. The change in mean trough FEV1 from baseline to Week 12 compared to placebo was assessed to evaluate the efficacy of ASMANEX HFA 100 mcg. The change from baseline to week 12 in the mean trough FEV1 was greater among patients receiving ASMANEX HFA 100 mcg 2 inhalations twice daily than among those receiving placebo (treatment difference from placebo 0.12 L and 95% confidence interval [0.05, 0.20]). Clinically judged deteriorations in asthma or reductions in lung function were also assessed to evaluate the efficacy of ASMANEX HFA 100 mcg. Deteriorations in asthma were defined as any of the following: a 20% decrease in FEV1; a 30% decrease in PEF on two or more consecutive days; emergency treatment, hospitalization, or treatment with systemic corticosteroids or other asthma medications not allowed per protocol. Sixty-five (34%) patients who received ASMANEX HFA 100 mcg reported an event compared to 109 (56%) patients who received placebo. Treatment of asthma patients with ASMANEX HFA 100 mcg, two inhalations twice daily also resulted in fewer nocturnal awakenings and improved morning peak flow compared to those who received placebo. Trial 2: Clinical Trial with ASMANEX HFA 200 mcg This 12-week randomized, double-blind, active-controlled trial also conducted as part of a mometasone furoate/formoterol fumarate combination product asthma program evaluated a total of 728 patients 12 years of age and older comparing ASMANEX HFA 200 mcg (n=240 patients), mometasone furoate/formoterol fumarate 200 mcg/5 mcg (n=255 patients), and mometasone furoate/formoterol fumarate 100 mcg/5 mcg (n=233 patients), each administered as 2 inhalations twice daily by metered dose inhalation aerosols. All other maintenance therapies were discontinued. This trial included a 2- to 3- week run-in period with ASMANEX HFA 200 mcg, 2 inhalations twice daily. Patients had persistent asthma and were uncontrolled on high-dose inhaled corticosteroids prior to study entry. Patients ranged from 12 to 84 years of age, 44% were male and 56% female, and 89% were Caucasian and 11% non- Caucasian. Mean FEV1 and mean percent predicted FEV1 values were similar among all treatment groups (2.05 L, 66%). The number of patients who discontinued the trial early due to treatment failure were 11 (5%) in the mometasone furoate/formoterol fumarate 100 mcg/5 mcg group, 8 (3%) in the mometasone furoate/formoterol fumarate 200 mcg/5 mcg group, and 13 (5%) in the ASMANEX HFA 200 mcg group. In order to assess the added benefit of a higher dose of mometasone in the 200 mcg/actuation mometasone furoate product compared to the lower dose 100 mcg/actuation product, trough FEV1 at 12 weeks was compared between the combination mometasone furoate/formoterol fumarate 200 mcg/5 mcg and 100 mcg/5 mcg treatment groups as a secondary endpoint. Improvement in trough FEV1 from baseline to week 12 in patients who received mometasone furoate 200 mcg in combination with formoterol fumarate 5 mcg was numerically greater than among patients who received mometasone furoate 100 mcg in combination with formoterol fumarate 5 mcg (treatment difference of 0.05 L and 95% confidence interval [-0.02, 0.10]). Other Studies In addition to Trial 1 and Trial 2, the safety and efficacy of mometasone furoate MDI 100 mcg and 200 mcg, in comparison to placebo were demonstrated in three other 12-week, placebo-controlled trials which evaluated the mean change in FEV1 from baseline as a primary endpoint.

Find Lowest Prices on NASONEX® (mometasone furoate monohydrate) Nasal Spray DESCRIPTION Mometasone furoate monohydrate, the active component of NASONEX Nasal Spray, 50 mcg, is an antiinflammatory corticosteroid having the chemical name, 9,21-Dichloro-11ß,17-dihydroxy-16α- methylpregna-1,4-diene-3,20-dione17-(2 furoate) monohydrate, and the following chemical structure: Mometasone furoate monohydrate is a white powder, with an empirical formula of C27H30C12O6•H2O, and a molecular weight of 539.45. It is practically insoluble in water; slightly soluble in methanol, ethanol, and isopropanol; soluble in acetone and chloroform; and freely soluble in tetrahydrofuran. Its partition coefficient between octanol and water is greater than 5000. NASONEX Nasal Spray 50 mcg is a metered-dose, manual pump spray unit containing an aqueous suspension of mometasone furoate monohydrate equivalent to 0.05% w/w mometasone furoate calculated on the anhydrous basis; in an aqueous medium containing glycerin, microcrystalline cellulose and carboxymethylcellulose sodium, sodium citrate, citric acid, benzalkonium chloride, and polysorbate 80. The pH is between 4.3 and 4.9.

Find Lowest Prices on ELOCON®  (mometasone furoate) Cream, 0.1% DESCRIPTION ELOCON (mometasone furoate) Cream, 0.1% contains mometasone furoate for topical use. Mometasone furoate is a synthetic corticosteroid with anti-inflammatory activity. Chemically, mometasone furoate is 9α,21-dichloro-11β,17-dihydroxy-16α-methylpregna-1,4-diene3,20-dione 17-(2-furoate), with the empirical formula C27 H30CI2O6, a molecular weight of 521.4 and the following structural formula: Mometasone furoate is a white to off-white powder practically insoluble in water, slightly soluble in octanol, and moderately soluble in ethyl alcohol. Each gram of ELOCON Cream, 0.1% contains 1 mg mometasone furoate in a white to off-white cream base of aluminum starch octenylsuccinate (Gamma Irradiated), hexylene glycol, hydrogenated soybean lecithin, phosphoric acid, purified water, titanium dioxide, white soft paraffin, and white wax.

Find Lowest Prices on ASMANEX® HFA 100 mcg (mometasone furoate) Oral Inhaler DESCRIPTION ASMANEX HFA is a metered dose inhaler for oral inhalation only, consisting of 100 mcg and 200 mcg of mometasone furoate per actuation. Mometasone furoate, the active component of ASMANEX HFA, is a corticosteroid having the chemical name 9,21-dichloro-11(Beta),17-dihydroxy-16 (alpha)-methylpregna-1,4-diene-3,20-dione 17-(2- furoate) with the following chemical structure: Mometasone furoate is a white powder with an empirical formula of C27H30Cl2O6, and molecular weight 521.44. It is practically insoluble in water; slightly soluble in methanol, ethanol, and isopropanol; soluble in acetone. Each ASMANEX HFA 100 mcg and 200 mcg is a hydrofluoroalkane (HFA-227: 1,1,1,2,3,3,3- heptafluoropropane) propelled pressurized metered dose inhaler containing sufficient amount of drug for 120 actuations [see HOW SUPPLIED/Storage and Handling]. After priming, each actuation of the inhaler delivers 115 or 225 mcg of mometasone furoate in 69.6 mg of suspension from the valve and delivers 100 or 200 mcg of mometasone furoate from the actuator. The actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between actuation of the device and inspiration through the delivery system. ASMANEX HFA also contains ethanol as a cosolvent and oleic acid as a surfactant. ASMANEX HFA should be primed before using for the first time by releasing 4 test sprays into the air, away from the face, shaking well before each spray. In cases where the inhaler has not been used for more than 5 days, prime the inhaler again by releasing 4 test sprays into the air, away from the face, shaking well before each spray.

INDICATIONS Treatment Of Allergic Rhinitis NASONEX® Nasal Spray 50 mcg is indicated for the treatment of the nasal symptoms of seasonal allergic and perennial allergic rhinitis, in adults and pediatric patients 2 years of age and older. Treatment Of Nasal Congestion Associated With Seasonal Allergic Rhinitis NASONEX Nasal Spray 50 mcg is indicated for the relief of nasal congestion associated with seasonal allergic rhinitis, in adults and pediatric patients 2 years of age and older. Prophylaxis Of Seasonal Allergic Rhinitis NASONEX Nasal Spray 50 mcg is indicated for the prophylaxis of the nasal symptoms of seasonal allergic rhinitis in adult and adolescent patients 12 years and older. Treatment Of Nasal Polyps NASONEX Nasal Spray 50 mcg is indicated for the treatment of nasal polyps in patients 18 years of age and older. DOSAGE AND ADMINISTRATION Administer NASONEX Nasal Spray 50 mcg by the intranasal route only. Prior to initial use of NASONEX Nasal Spray, 50 mcg, the pump must be primed by actuating ten times or until a fine spray appears. The pump may be stored unused for up to 1 week without repriming. If unused for more than 1 week, reprime by actuating two times, or until a fine spray appears. Treatment Of Allergic Rhinitis Adults And Adolescents 12 Years Of Age And Older: The recommended dose for treatment of the nasal symptoms of seasonal allergic and perennial allergic rhinitis is 2 sprays (50 mcg of mometasone furoate in each spray) in each nostril once daily (total daily dose of 200 mcg). Children 2 To 11 Years Of Age: The recommended dose for treatment of the nasal symptoms of seasonal allergic and perennial allergic rhinitis is 1 spray (50 mcg of mometasone furoate in each spray) in each nostril once daily (total daily dose of 100 mcg). Treatment Of Nasal Congestion Associated With Seasonal Allergic Rhinitis Adults And Adolescents 12 Years Of Age And Older: The recommended dose for treatment of nasal congestion associated with seasonal allergic rhinitis is two sprays (50 mcg of mometasone furoate in each spray) in each nostril once daily (total daily dose of 200 mcg). Children 2 To 11 Years Of Age: The recommended dose for treatment of nasal congestion associated with seasonal allergic rhinitis is one spray (50 mcg of mometasone furoate in each spray) in each nostril once daily (total daily dose of 100 mcg). Prophylaxis Of Seasonal Allergic Rhinitis Adults And Adolescents 12 Years Of Age And Older: The recommended dose for prophylaxis treatment of nasal symptoms of seasonal allergic rhinitis is 2 sprays (50 mcg of mometasone furoate in each spray) in each nostril once daily (total daily dose of 200 mcg). In patients with a known seasonal allergen that precipitates nasal symptoms of seasonal allergic rhinitis, prophylaxis with NASONEX Nasal Spray 50 mcg (200 mcg/day) is recommended 2 to 4 weeks prior to the anticipated start of the pollen season. Treatment Of Nasal Polyps Adults 18 Years Of Age And Older: The recommended dose for the treatment of nasal polyps is 2 sprays (50 mcg of mometasone furoate in each spray) in each nostril twice daily (total daily dose of 400 mcg). A dose of 2 sprays (50 mcg of mometasone furoate in each spray) in each nostril once daily (total daily dose of 200 mcg) is also effective in some patients. HOW SUPPLIED Dosage Forms And Strengths NASONEX Nasal Spray 50 mcg is a metered-dose, manual pump spray unit containing an aqueous suspension of mometasone furoate monohydrate equivalent to 0.05% w/w mometasone furoate calculated on the anhydrous basis. After initial priming (10 actuations), each actuation of the pump delivers a metered spray containing 100 mg or 100 microliter of suspension containing mometasone furoate monohydrate equivalent to 50 mcg of mometasone furoate calculated on the anhydrous basis. Each bottle of NASONEX Nasal Spray 50 mcg provides 120 sprays. Storage And Handling NASONEX (mometasone furoate monohydrate) Nasal Spray, 50 mcg is supplied in a white, high- density, polyethylene bottle fitted with a white metered-dose, manual spray pump, and blue cap. It contains 17 g of product formulation, 120 sprays, each delivering 50 mcg of mometasone furoate per actuation. (NDC 0085-1288-01). Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from light. When NASONEX Nasal Spray, 50 mcg is removed from its cardboard container, prolonged exposure of the product to direct light should be avoided. Brief exposure to light, as with normal use, is acceptable. SHAKE WELL BEFORE EACH USE. Keep out of reach of children. Manufactured by: MSD International GmbH (Singapore Branch), Singapore 638414, Singapore. Revised: Mar 2013

INDICATIONS ELOCON® Cream is a corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses in patients 2 years of age or older. DOSAGE AND ADMINISTRATION Apply a thin film of ELOCON Cream to the affected skin areas once daily. ELOCON Cream may be used in pediatric patients 2 years of age or older. Since safety and efficacy of ELOCON Cream have not been established in pediatric patients below 2 years of age; use in this age group is not recommended [see WARNINGS AND PRECAUTIONS and Use in Specific Populations]. Therapy should be discontinued when control is achieved. If no improvement is seen within 2 weeks, reassessment of diagnosis may be necessary. Safety and efficacy of ELOCON Cream in pediatric patients for more than 3 weeks of use have not been established. ELOCON Cream should not be used with occlusive dressings unless directed by a physician. ELOCON Cream should not be applied in the diaper area if the child still requires diapers or plastic pants, as these garments may constitute occlusive dressing. ELOCON Cream is for topical use only. It is not for oral, ophthalmic, or intravaginal use. Avoid use on the face, groin, or axillae. HOW SUPPLIED Dosage Forms And Strengths Cream, 0.1%. Each gram of ELOCON Cream contains 1 mg of mometasone furoate in a white to off-white smooth and homogenous cream base. Storage And Handling ELOCON Cream is white to off-white in color and supplied in 15-gram (NDC 0085-3149-01) and 50-gram (NDC 0085-3149-03) tubes. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Avoid excessive heat. Manufactured for : Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ 08889, USA. Manufactured by: Schering-Plough Labo NV Heist-op-den-Berg, Belgium. Revised: Apr 2013

INDICATIONS Treatment Of Asthma ASMANEX® HFA is indicated for the maintenance treatment of asthma as prophylactic therapy in patients 12 years of age and older. Important Limitations of Use ASMANEX HFA is NOT indicated for the relief of acute bronchospasm. DOSAGE AND ADMINISTRATION General ASMANEX HFA should be administered only by the orally inhaled route [see Instructions for Use in the PATIENT INFORMATION leaflet]. After each dose, the patient should be advised to rinse his/her mouth with water without swallowing. The cap from the mouthpiece of the actuator should be removed before using ASMANEX HFA. ASMANEX HFA should be primed before using for the first time by releasing 4 test sprays into the air, away from the face, shaking well before each spray. In cases where the inhaler has not been used for more than 5 days, prime the inhaler again by releasing 4 test sprays into the air, away from the face, shaking well before each spray. The ASMANEX HFA canister should only be used with the ASMANEX HFA actuator. The ASMANEX HFA actuator should not be used with any other inhalation drug product. Actuators from other products should not be used with the ASMANEX HFA canister. Dosing ASMANEX HFA should be administered as two inhalations twice daily every day (morning and evening) by the orally inhaled route. Shake well prior to each inhalation. The recommended doses for ASMANEX HFA treatment based on prior asthma therapy are provided in Table 1. TABLE 1: Recommended Dosages for ASMANEX HFA Treatment Previous Therapy Recommended Dose Inhaled medium-dose corticosteroids ASMANEX HFA 100 mcg, 2 inhalations twice daily Inhaled high-dose corticosteroids ASMANEX HFA 200 mcg, 2 inhalations twice daily Oral corticosteroids* ASMANEX HFA 200 mcg, 2 inhalations twice daily *For Patients Currently Receiving Chronic Oral Corticosteroid Therapy: Prednisone should be weaned slowly, beginning after at least 1 week of ASMANEX HFA therapy. Monitor patients carefully for signs of asthma instability, including serial objective measures of airflow, and for signs of adrenal insufficiency during steroid taper and following discontinuation of oral corticosteroid therapy [see WARNINGS AND PRECAUTIONS]. If a dosage regimen of ASMANEX HFA fails to provide adequate control of asthma, the therapeutic regimen should be re-evaluated and additional therapeutic options, e.g., replacing the current strength of ASMANEX HFA with a higher strength, initiating an inhaled corticosteroid and long-acting beta2-agonist combination product, or initiating oral corticosteroids, should be considered. The maximum daily recommended dose is two inhalations of ASMANEX HFA 200 mcg twice daily (maximum of 800 mcg a day). If symptoms arise between doses, an inhaled short-acting beta2-agonist should be taken for immediate relief. The maximum benefit may not be achieved for 1 week or longer after beginning treatment. Individual patients may experience a variable time to onset and degree of symptom relief. For patients who do not respond adequately after 2 weeks of therapy, higher strength may provide additional asthma control. After asthma stability has been achieved, it is desirable to titrate to the lowest effective dosage to reduce the possibility of side effects. HOW SUPPLIED Dosage Forms And Strengths ASMANEX HFA is a pressurized metered dose inhaler that is available in 2 strengths. ASMANEX HFA 100 mcg delivers 100 mcg of mometasone furoate per actuation. ASMANEX HFA 200 mcg delivers 200 mcg of mometasone furoate per actuation. ASMANEX HFA is available in two strengths and supplied in the following package size (Table 4): Table 4 Package NDC ASMANEX HFA 100 mcg 120 metered actuations 0085-4333-01 ASMANEX HFA 200 mcg 120 metered actuations 0085-4334-01 Each strength is supplied as a pressurized aluminum canister that has a blue plastic actuator integrated with a dose counter and a pink dust cap. Each canister has a net fill weight of 13 grams. Each inhaler is placed into a carton. Each carton contains 1 inhaler. Initially the dose counter will display “124” actuations. After the initial priming with 4 actuations, the dose counter will read “120” and the inhaler is now ready for use. Storage And Handling The ASMANEX HFA canister should only be used with the ASMANEX HFA actuator. The ASMANEX HFA actuator should not be used with any other inhalation drug product. Actuators from other products should not be used with the ASMANEX HFA canister. The canister should not be removed from the actuator because the correct amount of medication may not be discharged; the dose counter may not function properly; reinsertion may cause the dose counter to count down by 1 and discharge a puff. The correct amount of medication in each inhalation cannot be ensured after the labeled number of actuations from the canister has been used, even though the inhaler may not feel completely empty and may continue to operate. The inhaler should be discarded when the labeled number of actuations has been used (the dose counter will read “0”). Store at controlled room temperature 20-25°C (68-77°F); excursions permitted to 15-30°C (59- 86°F) [see USP Controlled Room Temperature]. For best results, the canister should be at room temperature before use. Shake well and remove the cap from the mouthpiece of the actuator before using. Keep out of reach of children. Avoid spraying in eyes. Contents Under Pressure: Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw container into fire or incinerator. Manufactured for: Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA. Manufactured by: 3M Health Care Ltd., Loughborough, United Kingdom. Revised: Aug 2015

PATIENT INFORMATION No information provided. Please refer to the WARNINGS AND PRECAUTIONS section.

OVERDOSE There are no data available on the effects of acute or chronic overdosage with NASONEX Nasal Spray 50 mcg. Because of low systemic bioavailability, and an absence of acute drug-related systemic findings in clinical studies, overdose is unlikely to require any therapy other than observation. Intranasal administration of 1600 mcg (4 times the recommended dose of NASONEX Nasal Spray 50 mcg for the treatment of nasal polyps in patients 18 years of age and older) daily for 29 days, to healthy human volunteers, showed no increased incidence of adverse events. Single intranasal doses up to 4000 mcg and oral inhalation doses up to 8000 mcg have been studied in human volunteers with no adverse effects reported. Chronic over dosage with any corticosteroid may result in signs or symptoms of hypercorticism [see WARNINGS AND PRECAUTIONS]. Acute overdosage with this dosage form is unlikely since one bottle of NASONEX Nasal Spray 50 mcg contains approximately 8500 mcg of mometasone furoate. CONTRAINDICATIONS NASONEX Nasal Spray is contraindicated in patients with known hypersensitivity to mometasone furoate or any of its ingredients.

OVERDOSE Topically applied ELOCON Cream can be absorbed in sufficient amounts to produce systemic effects [see WARNINGS AND PRECAUTIONS]. CONTRAINDICATIONS None.

OVERDOSE Chronic overdosage may result in signs/symptoms of hypercorticism [see WARNINGS AND PRECAUTIONS]. Single oral doses up to 8000 mcg of mometasone furoate have been studied on human volunteers with no adverse reactions reported. CONTRAINDICATIONS Status Asthmaticus ASMANEX HFA is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. Hypersensitivity ASMANEX HFA is contraindicated in patients with known hypersensitivity to mometasone furoate or any of the ingredients in ASMANEX HFA [see WARNINGS AND PRECAUTIONS].

SIDE EFFECTS Systemic and local corticosteroid use may result in the following: Epistaxis, ulcerations, Candida albicans infection, impaired wound healing [see WARNINGS AND PRECAUTIONS] Cataracts and glaucoma [see WARNINGS AND PRECAUTIONS] Immunosuppression [see WARNINGS AND PRECAUTIONS] Hypothalamic-pituitary-adrenal (HPA) axis effects, including growth reduction [see WARNINGS AND PRECAUTIONS, Use In Specific Populations] 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Allergic Rhinitis Adults And Adolescents 12 Years Of Age And Older In controlled US and international clinical studies, a total of 3210 adult and adolescent patients 12 years and older with allergic rhinitis received treatment with NASONEX Nasal Spray 50 mcg at doses of 50 to 800 mcg/day. The majority of patients (n=2103) were treated with 200 mcg/day. A total of 350 adult and adolescent patients have been treated for one year or longer. Adverse events did not differ significantly based on age, sex, or race. Four percent or less of patients in clinical trials discontinued treatment because of adverse events and the discontinuation rate was similar for the vehicle and active comparators. All adverse events (regardless of relationship to treatment) reported by 5% or more of adult and adolescent patients ages 12 years and older who received NASONEX Nasal Spray 50 mcg, 200 mcg/day vs. placebo and that were more common with NASONEX Nasal Spray 50 mcg than placebo, are displayed in TABLE 1 below. TABLE 1: ADULT AND ADOLESCENT PATIENTS 12 YEARS AND OLDER – ADVERSE EVENTS FROM CONTROLLED CLINICAL TRIALS IN SEASONAL ALLERGIC AND PERENNIAL ALLERGIC RHINITIS (PERCENT OF PATIENTS REPORTING) NASONEX 200 mcg (n=2103) VEHICLE PLACEBO (n=1671) Headache 26 22 Viral Infection 14 11 Pharyngitis 12 10 Epistaxis/Blood-Tinged Mucus 11 6 Coughing 7 6 Upper Respiratory Tract Infection 6 2 Dysmenorrhea 5 3 Musculoskeletal Pain 5 3 Sinusitis 5 3 Other adverse events which occurred in less than 5% but greater than or equal to 2% of adult and adolescent patients (ages 12 years and older) treated with NASONEX Nasal Spray 50 mcg, 200- mcg/day (regardless of relationship to treatment), and more frequently than in the placebo group included: arthralgia, asthma, bronchitis, chest pain, conjunctivitis, diarrhea, dyspepsia, earache, flu-like symptoms, myalgia, nausea, and rhinitis. Pediatric Patients <12 Years Of Age In controlled US and international studies, a total of 990 pediatric patients (ages 3 to 11 years) with allergic rhinitis received treatment with NASONEX Nasal Spray 50 mcg, at doses of 25 to 200 mcg/day. The majority of pediatric patients (n=720) were treated with 100 mcg/day. A total of 163 pediatric patients have been treated for one year or longer. Two percent or less of patients in clinical trials who received NASONEX Nasal Spray 50 mcg discontinued treatment because of adverse events and the discontinuation rate was similar for the placebo and active comparators. Adverse events which occurred in ≥5% of pediatric patients (ages 3 to 11 years) treated with NASONEX Nasal Spray 50 mcg, 100 mcg/day vs. placebo (regardless of relationship to treatment) and more frequently than in the placebo group included upper respiratory tract infection (5% in NASONEX Nasal Spray 50 mcg group vs. 4% in placebo) and vomiting (5% in NASONEX Nasal Spray 50 mcg group vs. 4% in placebo). Other adverse events which occurred in less than 5% but greater than or equal to 2% of pediatric patients (ages 3 to 11 years) treated with NASONEX Nasal Spray 50 mcg, 100 mcg/day vs. placebo (regardless of relationship to treatment) and more frequently than in the placebo group included: diarrhea, nasal irritation, otitis media, and wheezing. The adverse event (regardless of relationship to treatment) reported by 5% of pediatric patients ages 2 to 5 years who received NASONEX Nasal Spray, 50 mcg, 100 mcg/day in a clinical trial vs. placebo including 56 subjects (28 each NASONEX Nasal Spray, 50 mcg and placebo) and that was more common with NASONEX Nasal Spray, 50 mcg than placebo, included: upper respiratory tract infection (7% vs. 0%, respectively). The other adverse event which occurred in less than 5% but greater than or equal to 2% of mometasone furoate pediatric patients ages 2 to 5 years treated with 100 mcg doses vs. placebo (regardless of relationship to treatment) and more frequently than in the placebo group included: skin trauma. Nasal Polyps Adults 18 Years Of Age And Older In controlled clinical studies, the types of adverse events observed in patients with nasal polyps were similar to those observed for patients with allergic rhinitis. A total of 594 adult patients (ages 18 to 86 years) received NASONEX Nasal Spray 50 mcg at doses of 200 mcg once or twice daily for up to 4 months for treatment of nasal polyps. The overall incidence of adverse events for patients treated with NASONEX Nasal Spray 50 mcg was comparable to patients with the placebo except for epistaxis, which was 9% for 200 mcg once daily, 13% for 200 mcg twice daily, and 5% for the placebo. Nasal ulcers and nasal and oral candidiasis were also reported in patients treated with NASONEX Nasal Spray 50 mcg primarily in patients treated for longer than 4 weeks. Nasal Congestion Associated With Seasonal Allergic Rhinitis A total of 1008 patients aged 12 years and older received NASONEX Nasal Spray 50 mcg 200 mcg/day (n=506) or placebo (n=502) for 15 days. Adverse events that occurred more frequently in patients treated with NASONEX Nasal Spray 50 mcg than in patients with the placebo included sinus headache (1.2% in NASONEX Nasal Spray 50 mcg group vs. 0.2% in placebo) and epistaxis (1% in NASONEX Nasal Spray 50 mcg group vs. 0.2% in placebo) and the overall adverse event profile was similar to that observed in the other allergic rhinitis trials. Post-Marketing Experience The following adverse reactions have been identified during the post-marketing period for NASONEX Nasal Spray 50 mcg: nasal burning and irritation, anaphylaxis and angioedema, disturbances in taste and smell and nasal septal perforation. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted with NASONEX Nasal Spray 50 mcg. Inhibitors Of Cytochrome P450 3A4 Studies have shown that mometasone furoate is primarily and extensively metabolized in the liver of all species investigated and undergoes extensive metabolism to multiple metabolites. In vitro studies have confirmed the primary role of cytochrome CYP 3A4 in the metabolism of this compound. Coadministration with ketoconazole, a potent CYP 3A4 inhibitor, may increase the plasma concentrations of mometasone furoate [see CLINICAL PHARMACOLOGY].

SIDE EFFECTS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In controlled clinical trials involving 319 subjects, the incidence of adverse reactions associated with the use of ELOCON Cream was 1.6%. Reported reactions included burning, pruritus, and skin atrophy. Reports of rosacea associated with the use of ELOCON Cream have also been received. In controlled clinical trials (n=74) involving pediatric subjects 2 to 12 years of age, the incidence of adverse experiences associated with the use of ELOCON Cream was approximately 7%. Reported reactions included stinging, pruritus, and furunculosis. The following adverse reactions were reported to be possibly or probably related to treatment with ELOCON Cream during clinical trials in 4% of 182 pediatric subjects 6 months to 2 years of age: decreased glucocorticoid levels, 2; paresthesia, 2; folliculitis, 1; moniliasis, 1; bacterial infection, 1; skin depigmentation, 1. The following signs of skin atrophy were also observed among 97 subjects treated with ELOCON Cream in a clinical trial: shininess, 4; telangiectasia, 1; loss of elasticity, 4; loss of normal skin markings, 4; thinness, 1; and bruising, 1. The following additional local adverse reactions have been reported with topical corticosteroids, but may occur more frequently with the use of occlusive dressings. These reactions are: irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, striae, and miliaria. DRUG INTERACTIONS No drug-drug interaction studies have been conducted with ELOCON Cream.

SIDE EFFECTS Systemic and local corticosteroid use may result in the following: Candida albicans infection [see WARNINGS AND PRECAUTIONS] Immunosuppression [see WARNINGS AND PRECAUTIONS] Hypercorticism and adrenal suppression [see WARNINGS AND PRECAUTIONS] Growth effects in pediatrics [see WARNINGS AND PRECAUTIONS] Glaucoma and cataracts [see WARNINGS AND PRECAUTIONS] 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of ASMANEX HFA was evaluated in 2 randomized placebo and active-controlled trials of 12 and 26 weeks' duration, conducted as part of a mometasone furoate/formoterol fumarate combination product asthma program, which enrolled 1509 patients with persistent asthma. Patient ages ranged from 12 to 84 years of age, 41% were male and 59% female, 73% were Caucasian and 27% non-Caucasian. Of the total population enrolled in the 2 trials, 432 patients received two inhalations twice daily of either ASMANEX HFA, 100 mcg or 200 mcg/actuation. In the 26-week trial (Trial 1) 192 patients received two inhalations twice daily of ASMANEX HFA 100 mcg/actuation and 196 patients received placebo. In the 12 week trial (Trial 2) 240 patients received two inhalations twice daily of ASMANEX HFA 200 mcg/actuation and 233 and 255 patients received mometasone furoate and formoterol fumarate 100 mcg/5 mcg and 200 mcg/5 mcg/actuation combination products, respectively, as comparators. In these trials, the proportion of patients who discontinued study treatment early due to adverse reactions was 3% and 2% for ASMANEX HFA 100 and 200 mcg treated patients, respectively, and 4% for placebo-treated patients. Serious adverse reactions, whether considered drug-related or not by the investigators, which occurred more frequently in ASMANEX HFA-treated patients included colitis ulcerative, colonic polyp, chest pain, gastroenteritis, endometriosis, asthma, and hemoptysis; all events occurred at rates less than 1%. The incidence of treatment emergent adverse reactions associated with ASMANEX HFA are shown in Tables 2 and 3. These are based upon data from each of the 2 clinical trials of 12 or 26 weeks in duration in patients 12 years and older treated with two inhalations twice daily of ASMANEX HFA (100 mcg or 200 mcg), mometasone furoate/formoterol fumarate (100 mcg/5 mcg or 200 mcg/5 mcg), or placebo. TABLE 2: Trial 1: Treatment-Emergent Adverse Reactions Occurring at an Incidence of ≥ 3% and More Commonly than Placebo Over 26 Weeks ASMANEX HFA 100 mcg N=192 n (%) Placebo N=196 n (%) Nasopharyngitis 15 (8) 7 (4) Headache 10 (5) 7 (4) Influenza 7 (4) 5 (3) Sinusitis 6 (3) 2 (1) TABLE 3: Trial 2: Treatment-Emergent Adverse Reactions Occurring at an Incidence of ≥ 3% Over 12 Weeks ASMANEX HFA 200 mcg N=240 n (%) MF/F* 100/5 mcg N=233 n (%) MF/F* 200/5 mcg N=255 n (%) Nasopharyngitis 13 (5) 8 (3) 12 (5) Headache 8 (3) 10 (4) 5 (2) Bronchitis 6 (3) 2 (1) 7 (3) *MF/F = mometasone furoate/formoterol fumarate Oral candidiasis has been reported in clinical trials at an incidence of 0.5% in patients using ASMANEX HFA 100 mcg, 0.8% in patients using ASMANEX HFA 200 mcg and 0.5% in the placebo group. Postmarketing Experience There are no postmarketing adverse experiences reported to date with ASMANEX HFA. However, the postmarketing safety experience with mometasone furoate dry powder inhaler is relevant to ASMANEX HFA since they contain the same active ingredient. The following adverse reactions have been reported during post-approval use of mometasone furoate dry powder inhaler. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders Immediate and delayed hypersensitivity reactions including rash, pruritus, angioedema and anaphylactic reaction [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]. Respiratory, Thoracic and Mediastinal Disorders Asthma aggravation, which may include cough, dyspnea, wheezing and bronchospasm. DRUG INTERACTIONS In clinical trials, concurrent administration of ASMANEX HFA and other drugs, such as short-acting beta2-agonist and intranasal corticosteroids have not resulted in an increased frequency of adverse drug reactions. No formal drug interaction studies have been performed with ASMANEX HFA. Inhibitors Of Cytochrome P450 3A4 The main route of metabolism of corticosteroids, including mometasone furoate, is via CYP3A4. After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally inhaled mometasone furoate increased. Concomitant administration of CYP3A4 inhibitors may inhibit the metabolism of, and increase the systemic exposure to, mometasone furoate. Caution should be exercised when considering the coadministration of ASMANEX HFA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS Local Nasal Effects Epistaxis In clinical studies, epistaxis was observed more frequently in patients with allergic rhinitis with NASONEX Nasal Spray than those who received placebo [see ADVERSE REACTIONS]. Candida Infection In clinical studies with NASONEX Nasal Spray 50 mcg, the development of localized infections of the nose and pharynx with Candida albicans has occurred. When such an infection develops, use of NASONEX Nasal Spray 50 mcg should be discontinued and appropriate local or systemic therapy instituted, if needed. Nasal Septum Perforation Instances of nasal septum perforation have been reported following the intranasal application of corticosteroids. As with any long-term topical treatment of the nasal cavity, patients using NASONEX Nasal Spray 50 mcg over several months or longer should be examined periodically for possible changes in the nasal mucosa. Impaired Wound Healing Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal septum ulcers, nasal surgery, or nasal trauma should not use a nasal corticosteroid until healing has occurred. Glaucoma And Cataracts Nasal and inhaled corticosteroids may result in the development of glaucoma and/or cataracts. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. Glaucoma and cataract formation was evaluated in one controlled study of 12 weeks' duration and one uncontrolled study of 12 months' duration in patients treated with NASONEX Nasal Spray, 50 mcg at 200 mcg/day, using intraocular pressure measurements and slit lamp examination. No significant change from baseline was noted in the mean intraocular pressure measurements for the 141 NASONEX-treated patients in the 12-week study, as compared with 141 placebo-treated patients. No individual NASONEX-treated patient was noted to have developed a significant elevation in intraocular pressure or cataracts in this 12-week study. Likewise, no significant change from baseline was noted in the mean intraocular pressure measurements for the 139 NASONEX-treated patients in the 12-month study and again, no cataracts were detected in these patients. Nonetheless, nasal and inhaled corticosteroids have been associated with the development of glaucoma and/or cataracts. Hypersensitivity Reactions Hypersensitivity reactions including instances of wheezing may occur after the intranasal administration of mometasone furoate monohydrate. Discontinue NASONEX Nasal Spray if such reactions occur [see CONTRAINDICATIONS]. Immunosuppression Persons who are on drugs which 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 nonimmune children or adults on corticosteroids. In such children or adults who have not had these diseases, 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 exposed to chickenpox, prophylaxis with varicella zoster immune globin (VZIG) may be indicated. If 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. Corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculous infection of the respiratory tract, or in untreated fungal, bacterial, systemic viral infections, or ocular herpes simplex because of the potential for worsening of these infections. Hypothalamic-Pituitary-Adrenal Axis Effect Hypercorticism And Adrenal Suppression When intranasal steroids are used at higher than recommended dosages or in susceptible individuals at recommended dosages, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of NASONEX Nasal Spray should be discontinued slowly, consistent with accepted procedures for discontinuing oral corticosteroid therapy. Effect On Growth Corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth routinely of pediatric patients receiving NASONEX Nasal Spray. To minimize the systemic effects of intranasal corticosteroids, including NASONEX Nasal Spray, titrate each patient's dose to the lowest dosage that effectively controls his/her symptoms [see Use In Specific Populations]. Patient Counseling Information See FDA-approved labeling Local Nasal Effect Patients should be informed that treatment with NASONEX Nasal Spray 50 mcg may be associated with adverse reactions which include epistaxis (nose bleed) and nasal septum perforation. Candida infection may also occur. Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal septum ulcers, nasal surgery, or nasal trauma should not use a nasal corticosteroid until healing has occurred [see WARNINGS AND PRECAUTIONS]. Patients should be cautioned not to spray NASONEX Nasal Spray 50 mcg directly onto the nasal septum. Glaucoma And Cataracts Patients should be informed that nasal and inhaled corticosteroids may result in the development of glaucoma and/or cataracts. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. Patients should be cautioned not to spray NASONEX Nasal Spray 50 mcg into the eyes [see WARNINGS AND PRECAUTIONS]. Immunosuppression Persons who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles, and patients should also be advised that if they are exposed, medical advice should be sought without delay [see WARNINGS AND PRECAUTIONS]. Use Regularly For Best Effect Patients should use NASONEX Nasal Spray 50 mcg on a regular basis for optimal effect. Improvement in nasal symptoms of allergic rhinitis has been shown to occur within 1 to 2 days after initiation of dosing. Maximum benefit is usually achieved within 1 to 2 weeks after initiation of dosing. Patients should not increase the prescribed dosage but should contact their physician if symptoms do not improve, or if the condition worsens. Administration to young children should be aided by an adult. 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. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility 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 intranasal 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). Use In Specific Populations Pregnancy Teratogenic Effects Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. NASONEX Nasal Spray 50 mcg, like other corticosteroids, should be used during pregnancy only if the potential benefits justify the potential risk to the fetus. 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. In mice, mometasone furoate caused cleft palate at subcutaneous doses (less than the MRDID in adults on a mcg/m2 basis). Fetal survival was reduced at approximately 2 times the MRDID in adults on a mcg/m2 basis. No toxicity was observed at less than the MRDID in adults on a mcg/m2 basis. In rats, mometasone furoate produced umbilical hernia at topical dermal doses approximately 10 times the MRDID in adults on a mcg/m2 basis. A topical dermal dose 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, and hydrocephaly) at topical dermal doses 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 approximately 30 times the MRDID in adults on a mcg/m2 basis. At approximately 110 times the MRDID in adults on a mcg/m2 basis, most litters were aborted or resorbed. No toxicity was observed at 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, a dose 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. Nonteratogenic Effects Hypoadrenalism may occur in infants born to women receiving corticosteroids during pregnancy. Such infants should be carefully monitored. Nursing Mothers It is not known if mometasone furoate is excreted in human milk. Because other corticosteroids are excreted in human milk, caution should be used when NASONEX Nasal Spray, 50 mcg is administered to nursing women. Pediatric Use The safety and effectiveness of NASONEX Nasal Spray 50 mcg for allergic rhinitis in children 12 years of age and older have been established [see ADVERSE REACTIONS and Clinical Studies]. Use of NASONEX Nasal Spray 50 mcg for allergic rhinitis in pediatric patients 2 to 11 years of age is supported by safety and efficacy data from clinical studies. Seven hundred and twenty (720) patients 3 to 11 years of age with allergic rhinitis were treated with mometasone furoate nasal spray 50 mcg (100 mcg total daily dose) in controlled clinical trials [see ADVERSE REACTIONS and Clinical Studies]. Twenty-eight (28) patients 2 to 5 years of age with allergic rhinitis were treated with mometasone furoate nasal spray 50 mcg (100 mcg total daily dose) in a controlled trial to evaluate safety [see ADVERSE REACTIONS]. Safety and effectiveness of NASONEX Nasal Spray 50 mcg for allergic rhinitis in children less than 2 years of age have not been established. The safety and effectiveness of NASONEX Nasal Spray for the treatment of nasal polyps in children less than 18 years of age have not been established. One 4-month trial was conducted to evaluate the safety and efficacy of NASONEX in the treatment of nasal polyps in pediatric patients 6 to 17 years of age. The primary objective of the study was to evaluate safety; efficacy parameters were collected as secondary endpoints. A total of 127 patients with nasal polyps were randomized to placebo or NASONEX Nasal Spray 100 mcg once or twice daily (patients 6 to 11 years of age) or 200 mcg once or twice daily (patients 12 to 17 years of age). The results of this trial did not support the efficacy of NASONEX Nasal Spray in the treatment of nasal polyps in pediatric patients. The adverse events reported in this trial were similar to the adverse events reported in patients 18 years of age and older with nasal polyps. Controlled clinical studies have shown intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (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, including NASONEX Nasal Spray, 50 mcg, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of safe and effective noncorticosteroid treatment alternatives. To minimize the systemic effects of intranasal corticosteroids, including NASONEX Nasal Spray, 50 mcg, each patient should be titrated to his/her lowest effective dose. A clinical study to assess the effect of NASONEX Nasal Spray 50 mcg (100 mcg total daily dose) on growth velocity has been conducted in pediatric patients 3 to 9 years of age with allergic rhinitis. No statistically significant effect on growth velocity was observed for NASONEX Nasal Spray 50 mcg compared to placebo following one year of treatment. No evidence of clinically relevant HPA axis suppression was observed following a 30-minute cosyntropin infusion. The potential of NASONEX Nasal Spray 50 mcg to cause growth suppression in susceptible patients or when given at higher doses cannot be ruled out. Geriatric Use A total of 280 patients above 64 years of age with allergic rhinitis or nasal polyps (age range 64 to 86 years) have been treated with NASONEX Nasal Spray 50 mcg for up to 3 or 4 months, respectively. The adverse reactions reported in this population were similar in type and incidence to those reported by younger patients. Hepatic Impairment Concentrations of mometasone furoate appear to increase with severity of hepatic impairment [see CLINICAL PHARMACOLOGY].

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Effects on Endocrine System Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency. This may occur during treatment or after withdrawal of treatment. Manifestations of Cushing's syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment. Factors that predispose a patient using a topical corticosteroid to HPA axis suppression include the use of high-potency steroids, large treatment surface areas, prolonged use, use of occlusive dressings, altered skin barrier, liver failure and young age. Because of the potential for systemic absorption, use of topical corticosteroids may require that patients be periodically evaluated for HPA axis suppression. This may be done by using the adrenocorticotropic hormone (ACTH) stimulation test. In a study evaluating the effects of mometasone furoate cream on the HPA axis, 15 grams were applied twice daily for 7 days to six adult subjects with psoriasis or atopic dermatitis. The results show that the drug caused a slight lowering of adrenal corticosteroid secretion. If HPA axis suppression is noted, an attempt should be made to gradually withdraw the drug, to reduce the frequency of application, or to substitute a less potent corticosteroid. Recovery of HPA axis function is generally prompt upon discontinuation of topical corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur, requiring supplemental systemic corticosteroids. Pediatric patients may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios [see Use In Specific Populations]. Allergic Contact Dermatitis If irritation develops, ELOCON Cream should be discontinued and appropriate therapy instituted. Allergic contact dermatitis with corticosteroids is usually diagnosed by observing a failure to heal rather than noting a clinical exacerbation as with most topical products not containing corticosteroids. Such an observation should be corroborated with appropriate diagnostic patch testing. Concomitant Skin Infections If concomitant skin infections are present or develop, an appropriate antifungal or antibacterial agent should be used. If a favorable response does not occur promptly, use of ELOCON Cream should be discontinued until the infection has been adequately controlled. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential of ELOCON Cream. Long-term carcinogenicity studies of mometasone furoate were conducted by the inhalation route in rats and mice. In a 2-year carcinogenicity study in Sprague Dawley rats, mometasone furoate demonstrated no statistically significant increase of tumors at inhalation doses up to 67 mcg/kg (approximately 0.04 times the estimated maximum clinical topical dose from ELOCON Cream 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 0.05 times the estimated maximum clinical topical dose from ELOCON Cream 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, 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 in male or female rats by subcutaneous doses up to 15 mcg/kg (approximately 0.01 times the estimated maximum clinical topical dose from ELOCON Cream, on a mcg/m² basis). Use In Specific Populations Pregnancy Teratogenic Effects - Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Therefore, ELOCON Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. When administered to pregnant rats, rabbits, and mice, mometasone furoate increased fetal malformations. The doses that produced malformations also decreased fetal growth, as measured by lower fetal weights and/or delayed ossification. Mometasone furoate also caused dystocia and related complications when administered to rats during the end of pregnancy. In mice, mometasone furoate caused cleft palate at subcutaneous doses of 60 mcg/kg and above. Fetal survival was reduced at 180 mcg/kg. No toxicity was observed at 20 mcg/kg. (Doses of 20, 60, and 180 mcg/kg in the mouse are approximately 0.01, 0.02, and 0.05 times the estimated maximum clinical topical dose from ELOCON Cream on a mcg/m² basis.) In rats, mometasone furoate produced umbilical hernias at topical doses of 600 mcg/kg and above. A dose of 300 mcg/kg produced delays in ossification, but no malformations. (Doses of 300 and 600 mcg/kg in the rat are approximately 0.2 and 0.4 times the estimated maximum clinical topical dose from ELOCON Cream on a mcg/m² basis.) In rabbits, mometasone furoate caused multiple malformations (e.g., flexed front paws, gallbladder agenesis, umbilical hernia, hydrocephaly) at topical doses of 150 mcg/kg and above (approximately 0.2 times the estimated maximum clinical topical dose from ELOCON Cream on a mcg/m² basis). In an oral study, mometasone furoate increased resorptions and caused cleft palate and/or head malformations (hydrocephaly and domed head) at 700 mcg/kg. At 2800 mcg/kg most litters were aborted or resorbed. No toxicity was observed at 140 mcg/kg. (Doses at 140, 700, and 2800 mcg/kg in the rabbit are approximately 0.2, 0.9, and 3.6 times the estimated maximum clinical topical dose from ELOCON Cream 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 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. (Doses of 7.5 and 15 mcg/kg in the rat are approximately 0.005 and 0.01 times the estimated maximum clinical topical dose from ELOCON Cream on a mcg/m² basis.) Nursing Mothers Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when ELOCON Cream is administered to a nursing woman. Pediatric Use ELOCON Cream may be used with caution in pediatric patients 2 years of age or older, although the safety and efficacy of drug use for longer than 3 weeks have not been established. Since safety and efficacy of ELOCON Cream have not been established in pediatric patients below 2 years of age, its use in this age group is not recommended. In a pediatric trial, 24 atopic dermatitis subjects, of whom 19 subjects were age 2 to 12 years, were treated with ELOCON Cream once daily. The majority of subjects cleared within 3 weeks.ELOCON Cream caused HPA axis suppression in approximately 16% of pediatric subjects ages 6 to 23 months, who showed normal adrenal function by Cortrosyn test before starting treatment, and were treated for approximately 3 weeks over a mean body surface area of 41% (range 15%-94%). The criteria for suppression were: basal cortisol level of ≤ 5 mcg/dL, 30-minute post-stimulation level of ≤ 18 mcg/dL, or an increase of < 7 mcg/dL. Follow-up testing 2 to 4 weeks after trial completion, available for 5 of the subjects, demonstrated suppressed HPA axis function in 1 subject, using these same criteria. Long-term use of topical corticosteroids has not been studied in this population [see CLINICAL PHARMACOLOGY]. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of HPA axis suppression and Cushing's syndrome when they are treated with topical corticosteroids. They are, therefore, also at greater risk of adrenal insufficiency during and/or after withdrawal of treatment. Pediatric patients may be more susceptible than adults to skin atrophy, including striae, when they are treated with topical corticosteroids. Pediatric patients applying topical corticosteroids to greater than 20% of body surface are at higher risk of HPA axis suppression. HPA axis suppression, Cushing's syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in children include low plasma cortisol levels and an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. ELOCON Cream should not be used in the treatment of diaper dermatitis. Geriatric Use Clinical studies of ELOCON Cream included 190 subjects who were 65 years of age and over and 39 subjects who were 75 years of age and over. 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 patients. However, greater sensitivity of some older individuals cannot be ruled out.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Deterioration Of Asthma and Acute Episodes ASMANEX HFA is not indicated for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta2-agonist, not ASMANEX HFA, should be used to relieve acute symptoms such as shortness of breath. When prescribing ASMANEX HFA, the physician must also provide the patient with an inhaled, short-acting beta2-agonist (e.g., albuterol) for treatment of acute symptoms, despite regular twice-daily (morning and evening) use of ASMANEX HFA. Instruct patients to contact their physician immediately if episodes of asthma that are not responsive to bronchodilators occur during the course of treatment with ASMANEX HFA. During such episodes, patients may require therapy with oral corticosteroids. Local Effects In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans have occurred in patients treated with ASMANEX HFA. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while remaining on treatment with ASMANEX HFA therapy, but at times therapy with ASMANEX HFA may need to be interrupted. Advise patients to rinse the mouth after inhalation of ASMANEX HFA. Immunosuppression 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 who are not 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 exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG) may be indicated. If 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 infection of the respiratory tract, untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. Transferring Patients From Systemic Corticosteroid Therapy Particular care is needed for patients who are transferred from systemically active corticosteroids to ASMANEX HFA because deaths due to adrenal insufficiency have occurred in asthmatic patients 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 hypothalamicpituitary- adrenal (HPA) function. Patients who have been previously maintained on 20 mg or more per day 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 ASMANEX HFA may improve control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of corticosteroid systemically and does NOT provide the mineralocorticoid activity necessary for coping with these emergencies. During periods of stress or 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 medical identification card indicating that they may need supplementary systemic corticosteroids during periods of stress or severe asthma attack. Patients requiring oral or other systemic corticosteroids should be weaned slowly from oral or other systemic corticosteroid use after transferring to ASMANEX HFA. Lung function (FEV1 or PEF), betaagonist use, and asthma symptoms should be carefully monitored during withdrawal of oral or other systemic corticosteroids. In addition to monitoring asthma signs and symptoms, 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 ASMANEX HFA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, eczema, arthritis, and 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, and depression, despite maintenance or even improvement of respiratory function. Hypercorticism And Adrenal Suppression ASMANEX HFA will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since mometasone furoate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of ASMANEX 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. Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with ASMANEX 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 response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients, particularly when mometasone furoate is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of ASMANEX HFA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms. Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of ASMANEX HFA with ketoconazole, and other known strong cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to mometasone furoate may occur [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY]. Paradoxical Bronchospasm And Upper Airway Symptoms ASMANEX HFA may produce inhalation induced bronchospasm with an immediate increase in wheezing after dosing that may be life-threatening. If inhalation induced bronchospasm occurs, it should be treated immediately with an inhaled, short-acting bronchodilator. ASMANEX HFA should be discontinued immediately and alternative therapy instituted. Hypersensitivity Reactions Including Anaphylaxis Hypersensitivity reactions such as urticaria, flushing, allergic dermatitis, and bronchospasm, may occur after administration of ASMANEX HFA. Discontinue ASMANEX HFA if such reactions occur [see CONTRAINDICATIONS]. The following additional hypersensitivity reactions, such as rash, pruritus, angioedema, and anaphylactic reaction, have been reported after administration of mometasone furoate dry powder inhaler [see ADVERSE REACTIONS]. Reduction In Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids, including mometasone furoate. The clinical significance of small changes in BMD with regard to long-term outcomes, such as fracture, is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants and corticosteroids) should be monitored and treated with established standards of care. In a 2-year double-blind study in 103 male and female asthma patients 18 to 50 years of age previously maintained on bronchodilator therapy (Baseline FEV1 85%-88% predicted), treatment with mometasone furoate dry powder inhaler 200 mcg twice daily resulted in significant reductions in lumbar spine (LS) BMD at the end of the treatment period compared to placebo. The mean change from Baseline to Endpoint in the lumbar spine BMD was -0.015 (-1.43%) for the mometasone furoate dry powder inhaler group compared to 0.002 (0.25%) for the placebo group. In another 2-year double-blind study in 87 male and female asthma patients 18 to 50 years of age previously maintained on bronchodilator therapy (Baseline FEV1 82%-83% predicted), treatment with mometasone furoate dry powder inhaler 400 mcg twice daily demonstrated no statistically significant changes in lumbar spine BMD at the end of the treatment period compared to placebo. The mean change from Baseline to Endpoint in the lumbar spine BMD was -0.018 (-1.57%) for the mometasone furoate group compared to -0.006 (-0.43%) for the placebo group. Effect On Growth Orally inhaled corticosteroids, including ASMANEX HFA, may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving ASMANEX HFA routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including ASMANEX HFA, titrate each patient's dose to the lowest dosage that effectively controls his/her symptoms [see Use in Specific Populations]. Glaucoma And Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported following the use of long-term administration of inhaled corticosteroids, including mometasone furoate. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts [see ADVERSE REACTIONS]. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use). Not for Acute Symptoms Advise patients that ASMANEX HFA is not indicated to relieve acute asthma symptoms, and extra doses should not be used for that purpose. ASMANEX HFA is not a bronchodilator and should not be used to treat status asthmaticus or to relieve acute asthma symptoms. Acute asthma symptoms should be treated with an inhaled, short-acting beta2-agonist such as albuterol. Prescribe the patient with such medication and instruct the patient in how it should be used [see WARNINGS AND PRECAUTIONS]. Instruct patients to seek medical attention immediately if they experience any of the following: If their symptoms worsen Significant decrease in lung function as outlined by the physician If they need more inhalations of a short-acting beta2-agonist than usual Advise patients not to increase the dose or frequency of ASMANEX HFA. The daily dosage of ASMANEX HFA should not exceed two inhalations twice daily. If they miss a dose, instruct patients to take their next dose at the same time they normally do. Advise patients not to stop or reduce ASMANEX HFA therapy without physician/provider guidance since symptoms may recur after discontinuation. Local Effects Advise patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing with ASMANEX HFA therapy, but at times therapy with ASMANEX HFA may need to be temporarily interrupted under close medical supervision. Advise patients to rinse the mouth after inhalation of ASMANEX HFA [see WARNINGS AND PRECAUTIONS]. Immunosuppression Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physician 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 ASMANEX HFA may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, instruct 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 ASMANEX HFA [see WARNINGS AND PRECAUTIONS]. 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 and should be monitored and, where appropriate, be treated for this condition [see WARNINGS AND PRECAUTIONS]. Reduced Growth Velocity Inform patients that orally inhaled corticosteroids, including ASMANEX HFA, may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of pediatric patients taking corticosteroids by any route [see WARNINGS AND PRECAUTIONS]. Glaucoma and Cataracts Advise patients that long-term use of inhaled corticosteroids may increase the risk of some eye problems (glaucoma or cataracts); regular eye examinations should be considered [see WARNINGS AND PRECAUTIONS]. Hypersensitivity Reactions Including Anaphylaxis Advise patients that hypersensitivity reactions, such as urticaria, flushing, allergic dermatitis, bronchospasm, rash, pruritus, angioedema, and anaphylactic reaction, may occur after administration of ASMANEX HFA. Instruct patients to discontinue ASMANEX HFA if such reactions occur [see WARNINGS AND PRECAUTIONS]. Use Daily for Best Effect Advise patients to use ASMANEX HFA at regular intervals, since its effectiveness depends on regular use. Maximum benefit may not be achieved for 1 week or longer after starting treatment. If symptoms do not improve after 2 weeks of therapy or if the condition worsens, instruct patients to contact their physician. Instructions for Use Instruct patients regarding the following: Read the PATIENT INFORMATION before use and follow the Instructions for Use carefully. Remind patients to: Remove the cap from the mouthpiece of the actuator before use. Not remove the canister from the actuator. Not wash inhaler in water. The mouthpiece should be cleaned using a dry wipe after every 7 days of use. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility 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 14 times the MRHD on an AUC 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 9 times the MRHD on an AUC basis). Mometasone furoate increased chromosomal aberrations in an in vitro Chinese hamster ovary cell assay, but did not have this effect 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, a rat bone marrow chromosomal aberration assay, or a mouse male germcell 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 (approximately 8 times the MRHD on an AUC basis). Use In Specific Populations Pregnancy Teratogenic Effects Pregnancy Category C There are no adequate and well-controlled studies of ASMANEX HFA in pregnant women. Animal reproduction studies of mometasone furoate in mice, rats, and rabbits revealed evidence of teratogenicity. Because animal reproduction studies are not always predictive of human response, ASMANEX HFA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Teratogenic Effects When administered to pregnant mice, rats, and rabbits, mometasone furoate increased fetal malformations and decreased fetal growth (measured by lower fetal weights and/or delayed ossification). Dystocia and related complications were also observed when mometasone furoate was administered to rats late in gestation. However, experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroid exposure than humans. In a mouse reproduction study, subcutaneous mometasone furoate produced cleft palate at approximately one-third of the maximum recommended daily human dose (MRHD) on a mcg/m² basis and decreased fetal survival at approximately 1 times the MRHD. No toxicity was observed at approximately one-tenth of the MRHD on a mcg/m² basis. In a rat reproduction study, mometasone furoate produced umbilical hernia at topical dermal doses approximately 6 times the MRHD on a mcg/m² basis and delays in ossification at approximately 3 times the MRHD on a mcg/m² basis. In another study, rats received subcutaneous doses of mometasone furoate throughout pregnancy or late in gestation. Treated animals had prolonged and difficult labor, fewer live births, lower birth weight, and reduced early pup survival at a dose that was approximately 8 times the MRHD on an area under the curve (AUC) basis. Similar effects were not observed at approximately 4 times MRHD on an AUC basis. In rabbits, mometasone furoate caused multiple malformations (e.g., flexed front paws, gallbladder agenesis, umbilical hernia, hydrocephaly) at topical dermal doses approximately 3 times the MRHD on a mcg/m² basis. In an oral study, mometasone furoate increased resorptions and caused cleft palate and/or head malformations (hydrocephaly and domed head) at a dose less than the MRHD based on AUC. At a dose approximately 2 times the MRHD based on AUC, most litters were aborted or resorbed [see Nonclinical Toxicology]. Nonteratogenic Effects Hypoadrenalism may occur in infants born to women receiving corticosteroids during pregnancy. Infants born to mothers taking substantial corticosteroid doses during pregnancy should be monitored for signs of hypoadrenalism. Labor And Delivery There are no adequate and well-controlled human studies that have studied the effects of ASMANEX HFA during labor and delivery. Nursing Mothers It is not known whether ASMANEX HFA is excreted in human milk. Because other corticosteroids are excreted in human milk, caution should be exercised when ASMANEX HFA is administered to a nursing woman. Since there are no data from well-controlled human studies on the use of ASMANEX HFA on nursing mothers, a decision should be made whether to discontinue nursing or to discontinue ASMANEX HFA, taking into account the importance of ASMANEX HFA to the mother. Pediatric Use The safety and effectiveness of ASMANEX HFA have been established in patients 12 years of age and older in 2 clinical trials of 12 and 26 weeks in duration. In the 2 clinical trials, 32 patients 12 to 17 years of age were treated with ASMANEX HFA. No overall differences in effectiveness were observed between patients in this age group compared to those observed in patients 18 years of age and older. There were no obvious differences in the type or frequency of adverse drug reactions reported in this age group compared to patients 18 years of age and older. The safety and efficacy of ASMANEX HFA have not been established in children less than 12 years of age. Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. In these studies, the mean reduction in growth velocity was approximately 1 cm per year (range 0.3 to 1.8 per year) and appears 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 growth of children and adolescents receiving orally inhaled corticosteroids, including ASMANEX HFA, should be monitored routinely (e.g., via stadiometry). If a child or adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect should be considered. The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including ASMANEX HFA, each patient should be titrated to his/her lowest effective dose [see DOSAGE AND ADMINISTRATION]. Geriatric Use A total of 38 patients 65 years of age and older (3 of whom were 75 years and older) have been treated with ASMANEX HFA in 2 clinical trials of 12 and 26 weeks in duration. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Based on available data for ASMANEX HFA, no adjustment of dosage in geriatric patients is warranted. Hepatic Impairment Concentrations of mometasone furoate appear to increase with severity of hepatic impairment [see CLINICAL PHARMACOLOGY].