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«HIGHLIGHTS OF PRESCRIBING INFORMATION - WARNINGS AND PRECAUTIONS -  These highlights do not include all the information needed to use Candida ...»

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10 OVERDOSAGE 10 Chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.6)]. Because of low systemic bioavailability and an absence of acute drug-related systemic findings in clinical studies, acute overdose is unlikely to require any treatment other than observation. Single daily doses as high as 1200 mcg per day for 28 days were well tolerated and did not cause a significant reduction in plasma cortisol AUC (94% of placebo AUC). Single oral doses up to 8000 mcg have been studied on human volunteers with no adverse reactions reported.

11 DESCRIPTION Mometasone furoate, the active component of the ASMANEX TWISTHALER product, is a

corticosteroid with the chemical name 9,21-dichloro-11(Beta),17-dihydroxy-16(alpha)-methylpregnadiene-3,20-dione 17-(2-furoate) and the following chemical structure:

Mometasone furoate is a white powder with an empirical formula of C27H30Cl2O6, and molecular weight of 521.44 Daltons.

The ASMANEX TWISTHALER 110 mcg and 220 mcg products are cap-activated, inhalation-driven, multidose dry powder inhalers containing mometasone furoate and anhydrous lactose (which contains trace amounts of milk proteins).

Each actuation of the ASMANEX TWISTHALER 110 mcg or 220 mcg inhaler provides a measured dose of approximately 0.75 or 1.5 mg mometasone furoate inhalation powder, containing 110 or 220 mcg of mometasone furoate, respectively. This results in delivery of 100 or 200 mcg mometasone furoate from the mouthpiece, respectively, based on in vitro testing at flow rates of 30 L/min and 60 L/min with constant volume of 2 L. The amount of mometasone furoate emitted from the inhaler in vitro does not differ significantly for flow rates ranging from 28.3 L/min to 70 L/min at a constant volume of 2 L. However, the amount of drug delivered to the lung will depend on patient factors such as inspiratory flow and peak inspiratory flow through the device. In adult and adolescent patients (aged ≥12 years)

with varied asthma severity, mean peak inspiratory flow rate through the device was 69 L/min (range:

54-77 L/min). In pediatric patients (aged 5-12 years) diagnosed with asthma, mean peak inspiratory flow rate in the 5- to 8-year-old subgroup was 50 L/min (minimum of 46 L/min) and for the 9- to 12year-old subgroup was 60 L/min (minimum of 48 L/min).

12 CLINICAL PHARMACOLOGY

12.1 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.

Though effective for the treatment of asthma, corticosteroids do not affect asthma symptoms immediately. Maximum improvement in symptoms following inhaled administration of mometasone

–  –  –

12.2 Pharmacodynamics Adrenal Function: The effects of ASMANEX TWISTHALER on adrenal function have been evaluated in 2 clinical studies: 1 in adults 18 years of age and older and 1 in pediatric patients 6 to 11 years of age. Both clinical studies were specifically designed to assess the effect of ASMANEX TWISTHALER on adrenal function.

In a 29-day, randomized, double-blind, placebo-controlled study in 64 adult and adolescent patients 18 years of age and older with asthma, ASMANEX TWISTHALER 440 mcg twice daily and 880 mcg twice daily (twice the highest recommended daily dose) were compared to both placebo and prednisone 10 mg once daily as a positive control. The 30-minute post-Cosyntropin stimulation serum cortisol concentration on Day 29 was 23.2 mcg/dL for the ASMANEX 440 mcg twice daily group (n=16) and

20.8 mcg/dL for the ASMANEX 880 mcg twice daily group (n=16), compared to 14.5 mcg/dL for the oral prednisone 10-mg group (n=16) and 25 mcg/dL for the placebo group (n=16). The difference between ASMANEX 880 mcg twice daily (twice the maximum recommended dose) and placebo was statistically significant.

In a 29-day, randomized, double-blind, placebo-controlled, parallel-group clinical trial in 50 pediatric patients 6 to 11 years of age with asthma, ASMANEX TWISTHALER 110 mcg twice daily, 220 mcg twice daily, and 440 mcg twice daily (2-8 times the highest pediatric daily recommended daily dose) were compared to placebo. HPA-axis function was assessed by 12-hour plasma cortisol AUC and 24hour urinary-free cortisol concentrations. After 29 days of treatment, the mean changes in plasma cortisol AUC0-12h from baseline were -0.11, -19.5, -21.3, and -3.47 mcg•hr/dL for the treatment groups of ASMANEX TWISTHALER 110 mcg twice daily (n=12), 220 mcg twice daily (n=12), 440 mcg twice daily (n=11), and placebo (n=7), respectively.





The mean differences from placebo in the groups treated with ASMANEX TWISTHALER 110 mcg twice daily, 220 mcg twice daily, and 440 mcg twice daily were 3.4 mcg•hr/dL (95% CI:

-14.0, 20.7), -16.0 mcg•hr/dL (95% CI:

-33.9, 1.9), and -17.9 mcg•hr/dL (95% CI:

-35.8, 0.0), respectively. For 24-hour urinary-free cortisol, after 29 days of treatment, the mean changes from baseline were -1.53, -1.33, -6.70, and -4.68 mcg/day for the groups treated with ASMANEX TWISTHALER 110 mcg twice daily (n=12), 220 mcg twice daily (n=12), 440 mcg twice daily (n=12), and placebo (n=10), respectively. The mean differences in urinary-free cortisol changes from baseline compared to placebo were 3.1 mcg/day (95% CI:

-3.3, 9.6), 3.3 mcg/day (95% CI:

-3.0, 9.7), and -2.0 mcg/day (95% CI:

-8.6, 4.6) for the groups treated with 110 mcg twice daily, 220 mcg twice daily, and 440 mcg twice daily, respectively.

12.3 Pharmacokinetics Absorption: Following a 1000 mcg inhaled dose of tritiated mometasone furoate inhalation powder to 6 healthy human subjects, plasma concentrations of unchanged mometasone furoate were shown to be very low compared to the total radioactivity in plasma. Following an inhaled single 400 mcg dose of ASMANEX TWISTHALER treatment to 24 healthy subjects, plasma concentrations for most subjects were near or below the lower limit of quantitation for the assay (50 pcg/mL). The mean absolute systemic bioavailability of the above single inhaled 400 mcg dose, compared to an intravenous 400 mcg dose of mometasone furoate, was determined to be less than 1%. Following administration of the recommended highest inhaled dose (400 mcg twice daily) to 64 patients for 28 days, concentration-time profiles were discernible, but with large intersubject variability. The coefficient of variation for Cmax and AUC ranged from approximately 50% to 100%. The mean peak plasma concentrations at steady state ranged from approximately 94 to 114 pcg/mL and the mean time to peak levels ranged from approximately 1.0 to 2.5 hours.

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 terminal half-life of about 5 hours and the 12 mean steady-state volume of distribution of 152 L. The in vitro protein binding for mometasone furoate was reported to be 98% to 99% (in a concentration range of 5-500 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 CYP 3A4 in the metabolism of this compound; however, no major metabolites were identified.

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.

Special 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 50-105 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 (8.4)].

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 Interaction: 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).

13 NONCLINICAL TOXICOLOGY

13.1 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 8 times the maximum recommended daily inhalation dose in adults on an AUC basis and 2 times the maximum recommended daily inhalation dose in pediatric patients based on an 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 10 times the maximum recommended daily inhalation dose in adults on an AUC basis and 2 times the maximum recommended daily inhalation dose in pediatric patients based on an mcg/m2 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

–  –  –

In reproductive studies in rats, impairment of fertility was not produced by subcutaneous doses up to 15 mcg/kg (approximately 6 times the maximum recommended daily inhalation dose in adults on an AUC basis).

13.2 Animal Toxicology and/or Pharmacology Reproductive Toxicology Studies: In mice, mometasone furoate caused cleft palate at subcutaneous doses of 60 mcg/kg and above (less than the maximum recommended daily inhalation dose in adults on an mcg/m2 basis). Fetal survival was reduced at 180 mcg/kg (approximately equal to the maximum recommended daily inhalation dose in adults on an mcg/m2 basis). No toxicity was observed at 20 mcg/kg (less than the maximum recommended daily inhalation dose in adults on an mcg/m2 basis).

In rats, mometasone furoate produced umbilical hernia at topical dermal doses of 600 mcg/kg and above (approximately 6 times the maximum recommended daily inhalation dose in adults on an mcg/m2 basis). A dose of 300 mcg/kg (approximately 3 times the maximum recommended daily inhalation dose in adults on an 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 6 times the maximum recommended daily inhalation dose in adults 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 3 times the maximum recommended daily inhalation dose in adults 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 maximum recommended daily inhalation dose in adults on an 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 maximum recommended daily inhalation dose in adults on an area under the curve [AUC] basis). At 2800 mcg/kg (approximately 2 times the maximum recommended daily inhalation dose in adults on an AUC basis) most litters were aborted or resorbed. No toxicity was observed at 140 mcg/kg (less than the maximum recommended daily inhalation dose in adults on an AUC basis).

14 CLINICAL STUDIES



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