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Veramyst

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Veramyst

Veramyst

CLINICAL PHARMACOLOGY

Mechanism of Action

Fluticasone furoate is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. The precise mechanism through which fluticasone furoate affects rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as NFkB, and inhibition of antigen-induced lung eosinophilia in sensitized rats.

Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. The clinical relevance of these findings is unknown.

Pharmacodynamics

Adrenal Function

The effects of VERAMYST Nasal Spray on adrenal function have been evaluated in 4 controlled clinical trials in patients with perennial allergic rhinitis. Two 6-week clinical trials were designed specifically to assess the effect of VERAMYST Nasal Spray on the HPA axis with assessments of both 24-hour urinary cortisol excretion and serum cortisol levels in domiciled patients. In addition, one 52-week safety study and one 12-week safety and efficacy study included assessments of 24-hour urinary cortisol excretion. Details of the studies and results are described below. In all 4 studies, since serum fluticasone determinations were generally below the limit of quantification, compliance was assured by efficacy assessments.

Clinical Trials Specifically Designed to Assess Hypothalamic-Pituitary-Adrenal Axis Effect

In a 6-week randomized, double-blind, parallel-group study in adult and adolescent patients aged 12 years and older with perennial allergic rhinitis, VERAMYST Nasal Spray 110 mcg was compared with both placebo nasal spray and prednisone as a positive-control group that received prednisone 10 mg orally once daily for the final 7 days of the treatment period. Adrenal function was assessed by 24-hour urinary cortisol excretion before and after 6 weeks of treatment and by serial serum cortisol levels. Patients were domiciled for collection of 24-hour urinary cortisol. After 6 weeks of treatment, there was a change from baseline in the mean 24-hour urinary cortisol excretion in the group treated with VERAMYST Nasal Spray (n = 43) of -1.16 mcg/day compared with -3.48 mcg/day in the placebo group (n = 42). The difference from placebo in the group treated with VERAMYST Nasal Spray was 2.32 mcg/day (95% CI: -6.76, 11.39). Urinary cortisol data were not available for the positive-control (prednisone) treatment group. For serum cortisol levels, after 6 weeks of treatment there was a change from baseline in the mean (0-24 hours) of -0.38 and 0.08 mcg/dL for the group treated with VERAMYST Nasal Spray (n = 43) and the placebo group (n = 44), respectively, with a difference between the group treated with VERAMYST Nasal Spray and the placebo group of -0.47 mcg/dL (95% CI: -1.31, 0.37). For comparison, in the positive-control (prednisone, n = 12) treatment group, there was a change in mean serum cortisol (0-24 hours) from baseline of -4.49 mcg/dL with a difference between the prednisone and placebo group of -4.57 mcg/dL (95% CI: -5.83, -3.31).

The second 6-week study conducted in children aged 2 to 11 years was of similar design to the adult study, including adrenal function assessments, but did not include a prednisone positive-control arm. Patients were treated once daily with VERAMYST Nasal Spray 110 mcg or placebo nasal spray. After 6 weeks of treatment, there was a change in the mean 24-hour urinary cortisol excretion in the group treated with VERAMYST Nasal Spray (n = 43) of 0.49 mcg/day compared with 1.92 mcg/day in the placebo group (n = 41), with a difference between the group treated with VERAMYST Nasal Spray and the placebo group of -1.43 mcg/day (95% CI: -5.21, 2.35). For serum cortisol levels, after 6 weeks, there was a change from baseline in mean (0-24 hours) of -0.34 and -0.23 mcg/dL for the group treated with VERAMYST Nasal Spray (n = 48) and for the placebo group (n = 47), respectively, with a difference between the group treated with VERAMYST Nasal Spray and the placebo group of -0.11 mcg/dL (95% CI: -0.88, 0.66).

Additional Hypothalamic-Pituitary-Adrenal Axis Assessments

In the 52-week safety trial in adolescents and adults aged 12 years and older with perennial allergic rhinitis, VERAMYST Nasal Spray 110 mcg (n = 605) was compared with placebo nasal spray (n = 201). Adrenal function was assessed by 24-hour urinary cortisol excretion in a subset of patients who received VERAMYST Nasal Spray (n = 370) or placebo (n = 120) before and after 52 weeks of treatment. After 52 weeks of treatment, the mean change from baseline 24-hour urinary cortisol excretion was 5.84 mcg/day in the group treated with VERAMYST Nasal Spray and 3.34 mcg/day in the placebo group. The difference from placebo in mean change from baseline 24-hour urinary cortisol excretion was 2.50 mcg/day (95% CI: -5.49, 10.49).

In the 12-week safety and efficacy trial in children aged 2 to 11 years with perennial allergic rhinitis, VERAMYST Nasal Spray 55 mcg (n = 185) and VERAMYST Nasal Spray 110 mcg (n = 185) were compared with placebo nasal spray (n = 188). Adrenal function was assessed by measurement of 24-hour urinary free cortisol in a subset of patients who were aged 6 to 11 years (103 to 109 patients per group) before and after 12 weeks of treatment. After 12 weeks of treatment, there was a decrease in mean 24-hour urinary cortisol excretion from baseline in the group treated with VERAMYST Nasal Spray 55 mcg (n = 109) of -2.93 mcg/day and in the group treated with VERAMYST Nasal Spray 110 mcg (n = 103) of -2.07 mcg/day compared with an increase in the placebo group (n = 107) of 0.08 mcg/day. The difference from placebo in mean change from baseline in 24-hour urinary cortisol excretion for the group treated with VERAMYST Nasal Spray 55 mcg was -3.01 mcg/day (95% CI: -6.16, 0.13) and -2.14 mcg/day (95% CI: -5.33, 1.04) for the group treated with VERAMYST Nasal Spray 110 mcg.

When the results of the HPA axis assessments described above are taken as a whole, an effect of intranasal fluticasone furoate on adrenal function cannot be ruled out, especially in pediatric patients.

Cardiac Effects

A QT/QTc study did not demonstrate an effect of fluticasone furoate administration on the QTc interval. The effect of a single dose of 4,000 mcg of orally inhaled fluticasone furoate on the QTc interval was evaluated over 24 hours in 40 healthy male and female subjects in a placebo and positive (a single dose of 400 mg oral moxifloxacin) controlled cross-over study. The QTcF maximal mean change from baseline following fluticasone furoate was similar to that observed with placebo with a treatment difference of 0.788 msec (90% CI: -1.802, 3.378). In contrast, moxifloxacin given as a 400-mg tablet resulted in prolongation of the QTcF maximal mean change from baseline compared with placebo with a treatment difference of 9.929 msec (90% CI: 7.339, 12.520). While a single dose of fluticasone furoate had no effect on the QTc interval, the effects of fluticasone furoate may not be at steady state following single dose. The effect of fluticasone furoate on the QTc interval following multiple dose administration is unknown.

Pharmacokinetics

Absorption

Following intranasal administration of fluticasone furoate, most of the dose is eventually swallowed and undergoes incomplete absorption and extensive first-pass metabolism in the liver and gut, resulting in negligible systemic exposure. At the highest recommended intranasal dosage of 110 mcg once daily for up to 12 months in adults and up to 12 weeks in children, plasma concentrations of fluticasone furoate are typically not quantifiable despite the use of a sensitive HPLC-MS/MS assay with a lower limit of quantification (LOQ) of 10 pg/mL. However, in a few isolated cases (<0.3%) fluticasone furoate was detected in high concentrations above 500 pg/mL, and in a single case the concentration was as high as 1,430 pg/mL in the 52-week study. There was no relationship between these concentrations and cortisol levels in these subjects. The reasons for these high concentrations are unknown.

Absolute bioavailability was evaluated in 16 male and female subjects following supratherapeutic dosages of fluticasone furoate (880 mcg given intranasally at 8-hour intervals for 10 doses, or 2,640 mcg/day). The average absolute bioavailability was 0.50% (90% CI: 0.34%, 0.74%).

Due to the low bioavailability by the intranasal route, the majority of the pharmacokinetic data was obtained via other routes of administration. Studies using oral solution and intravenous dosing of radiolabeled drug have demonstrated that at least 30% of fluticasone furoate is absorbed and then rapidly cleared from plasma. Oral bioavailability is on average 1.26%, and the majority of the circulating radioactivity is due to inactive metabolites.

Distribution

Following intravenous administration, the mean volume of distribution at steady state is 608 L.

Binding of fluticasone furoate to human plasma proteins is greater than 99%.

Metabolism

In vivo studies have revealed no evidence of cleavage of the furoate moiety to form fluticasone. Fluticasone furoate is cleared (total plasma clearance of 58.7 L/h) from systemic circulation principally by hepatic metabolism via CYP3A4. The principal route of metabolism is hydrolysis of the S-fluoromethyl carbothioate function to form the inactive 17β-carboxylic acid metabolite.

Elimination

Fluticasone furoate and its metabolites are eliminated primarily in the feces, accounting for approximately 101% and 90% of the orally and intravenously administered dose, respectively. Urinary excretion accounted for approximately 1% and 2% of the orally and intravenously administered dose, respectively. The elimination phase half-life averaged 15.1 hours following intravenous administration.

Population Pharmacokinetics

Fluticasone furoate is typically not quantifiable in plasma following intranasal dosing of 110 mcg once daily with the exception of isolated cases of very high plasma levels (see Absorption). Overall, quantifiable levels (>10 pg/mL) were observed in <31% of patients aged 12 years and older and in <16% of children (aged 2 to 11 years) following intranasal dosing of 110 mcg once daily and in <7% of children following intranasal dosing of 55 mcg once daily. There was no evidence to suggest that the presence or absence of detectable levels of fluticasone furoate was related to gender, age, or race.

Hepatic Impairment

Reduced liver function may affect the elimination of corticosteroids. Since fluticasone furoate undergoes extensive first-pass metabolism by the hepatic CYP3A4, the pharmacokinetics of fluticasone furoate may be altered in patients with hepatic impairment. A study of a single 400-mcg dose of orally inhaled fluticasone furoate in patients with moderate hepatic impairment (Child-Pugh Class B) resulted in increased C max (42%) and AUC(0-∞) (172%), resulting in an approximately 20% reduction in serum cortisol level in patients with hepatic impairment compared with healthy subjects. The systemic exposure would be expected to be higher than that observed had the study been conducted after multiple doses and/or in patients with severe hepatic impairment. Therefore, use VERAMYST Nasal Spray with caution in patients with severe hepatic impairment.

Renal Impairment

Fluticasone furoate is not detectable in urine from healthy subjects following intranasal dosing. Less than 1% of dose-related material is excreted in urine. No dosage adjustment is required in patients with renal impairment.

Clinical Studies

Seasonal and Perennial Allergic Rhinitis

Adult and Adolescent Patients Aged 12 Years and Older

The efficacy and safety of VERAMYST Nasal Spray was evaluated in 5 randomized, double-blind, parallel-group, multicenter, placebo-controlled clinical trials of 2 to 4 weeks' duration in adult and adolescent patients aged 12 years and older with symptoms of seasonal or perennial allergic rhinitis. The 5 clinical trials included one 2-week dose-ranging trial in patients with seasonal allergic rhinitis, three 2-week confirmatory efficacy trials in patients with seasonal allergic rhinitis, and one 4-week efficacy trial in patients with perennial allergic rhinitis. These trials included 1,829 patients (697 males and 1,132 females). About 75% of patients were Caucasian, and the mean age was 36 years. Of these patients, 722 received VERAMYST Nasal Spray 110 mcg once daily administered as 2 sprays in each nostril.

Assessment of efficacy was based on total nasal symptom score (TNSS). TNSS is calculated as the sum of the patients' scoring of the 4 individual nasal symptoms (rhinorrhea, nasal congestion, sneezing, and nasal itching) on a 0 to 3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe) as reflective (rTNSS) or instantaneous (iTNSS). rTNSS required the patients to record symptom severity over the previous 12 hours; iTNSS required patients to record symptom severity at the time immediately prior to the next dose. Morning and evening rTNSS scores were averaged over the treatment period and the difference from placebo in the change from baseline rTNSS was the primary efficacy endpoint. The morning iTNSS (AM iTNSS) reflects the TNSS at the end of the 24-hour dosing interval and is an indication of whether the effect was maintained over the 24-hour dosing interval.

Additional secondary efficacy variables were assessed, including the total ocular symptom score (TOSS) and the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). TOSS is calculated as the sum of the patients' scoring of the 3 individual ocular symptoms (itching/burning, tearing/watering, and redness) on a 0 to 3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe) as reflective (rTOSS) or instantaneous scores (iTOSS). To assess efficacy, rTOSS and AM iTOSS were evaluated as described above for the TNSS. Patients' perceptions of disease-specific quality of life were evaluated through use of the RQLQ, which assesses the impact of allergic rhinitis treatment through 28 items in 7 domains (activities, sleep, non-nose/eye symptoms, practical problems, nasal symptoms, eye symptoms, and emotional) on a 7-point scale where 0 = no impairment and 6 = maximum impairment. An overall RQLQ score is calculated from the mean of all items in the instrument. An absolute difference of ≥0.5 in mean change from baseline over placebo is considered the minimally important difference (MID) for the RQLQ.

Dose-Ranging Trial

The dose-ranging trial was a 2-week trial that evaluated the efficacy of 4 dosages of fluticasone furoate nasal spray (440, 220, 110, and 55 mcg) in patients with seasonal allergic rhinitis. In this trial, each of the 4 dosages of fluticasone furoate nasal spray demonstrated greater decreases in the rTNSS than placebo, and the difference was statistically significant (Table 3).

Table 3: Mean Change From Baseline in Reflective Total Nasal Symptom Score Over 2 Weeks in Patients With Seasonal Allergic Rhinitis

Treatment n Baseline (AM + PM) Change From Baseline Difference From Placebo
LS Mean 95% CI P Value
Fluticasone furoate 440 mcg 130 9.6 -4.02 -2.19 -2.75, -1.62 <0.001
Fluticasone furoate 220 mcg 129 9.5 -3.19 -1.36 -1.93, -0.79 <0.001
Fluticasone furoate 110 mcg 127 9.5 -3.84 -2.01 -2.58, -1.44 <0.001
Fluticasone furoate 55 mcg 125 9.6 -3.50 -1.68 -2.25, -1.10 <0.001
Placebo 128 9.6 -1.83      

Each of the 4 dosages of fluticasone furoate nasal spray also demonstrated greater decreases in the AM iTNSS than placebo, and the difference between each of the 4 fluticasone furoate treatment groups and placebo was statistically significant, indicating that the effect was maintained over the 24-hour dosing interval.

Seasonal Allergic Rhinitis Trials

Three clinical trials were designed to evaluate the efficacy of VERAMYST Nasal Spray 110 mcg once daily compared with placebo in patients with seasonal allergic rhinitis over a 2-week treatment period. In all 3 trials, VERAMYST Nasal Spray 110 mcg demonstrated a greater decrease from baseline in the rTNSS and AM iTNSS than placebo, and the difference from placebo was statistically significant. In terms of ocular symptoms, in all 3 seasonal allergic rhinitis trials, VERAMYST Nasal Spray 110 mcg demonstrated a greater decrease from baseline in the rTOSS than placebo and the difference from placebo was statistically significant. For the RQLQ in all 3 seasonal allergic rhinitis trials, VERAMYST Nasal Spray 110 mcg demonstrated greater decrease from baseline in the overall RQLQ than placebo, and the difference from placebo was statistically significant. The difference in the overall RQLQ score mean change from baseline between the groups treated with VERAMYST Nasal Spray and placebo ranged from -0.60 to -0.70 in the 3 trials, meeting the minimally important difference criterion. Table 4 displays the efficacy results from a representative trial in patients with seasonal allergic rhinitis.

Perennial Allergic Rhinitis Trials

One clinical trial was designed to evaluate the efficacy of VERAMYST Nasal Spray 110 mcg once daily compared with placebo in patients with perennial allergic rhinitis over a 4-week treatment period. VERAMYST Nasal Spray 110 mcg demonstrated a greater decrease from baseline in the rTNSS and AM iTNSS than placebo, and the difference from placebo was statistically significant. Similar to patients with seasonal allergic rhinitis, the improvement of nasal symptoms with VERAMYST Nasal Spray in patients with perennial allergic rhinitis persisted for a full 24 hours, as evaluated by AM iTNSS immediately prior to the next dose. However, unlike the trials in patients with seasonal allergic rhinitis, patients with perennial allergic rhinitis who were treated with VERAMYST Nasal Spray 110 mcg did not demonstrate statistically significant improvement from baseline in rTOSS or in disease-specific quality of life as measured by the RQLQ compared with placebo. In addition, the overall RQLQ score mean change from baseline difference between the group treated with VERAMYST Nasal Spray and the placebo group was -0.23, which did not meet the minimally important difference of ≥0.5. Table 4 displays the efficacy results from the clinical trial in patients with perennial allergic rhinitis.

Table 4: Mean Changes in Efficacy Variables in Adult and Adolescent Patients With Seasonal or Perennial Allergic Rhinitis

Treatment n Baseline Change From Baseline – LS Mean Difference From Placebo
LS Mean 95% CI P Value
Reflective Total Nasal Symptom Scores
Seasonal allergic rhinitis trial
  Fluticasone furoate 110 mcg 151 9.6 -3.55 -1.47 -2.01, -0.94 <0.001
  Placebo 147 9.9 -2.07
Perennial allergic rhinitis trial
  Fluticasone furoate 110 mcg 149 8.6 -2.78 -0.71 -1.20, -0.21 0.005
  Placebo 153 8.7 -2.08
Instantaneous Total Nasal Symptom Scores
Seasonal allergic rhinitis trial
  Fluticasone furoate 110 mcg 151 9.4 -2.90 -1.38 -1.90, -0.85 <0.001
  Placebo 147 9.3 -1.53
Perennial allergic rhinitis trial
  Fluticasone furoate 110 mcg 149 8.2 -2.45 -0.71 -1.20, -0.21 0.006
  Placebo 153 8.3 -1.75
Reflective Total Ocular Symptom Scores
Seasonal allergic rhinitis trial
  Fluticasone furoate 110 mcg 151 6.6 -2.23 -0.60 -1.01, -0.19 0.004
   Placebo 147 6.5 -1.63
Perennial allergic rhinitis trial
  Fluticasone furoate 110 mcg 149 4.8 -1.39 -0.15 -0.52, 0.22 0.428
  Placebo 153 5.0 -1.24
Rhinoconjunctivitis Quality of Life Questionnaire
Seasonal allergic rhinitis trial
  Fluticasone furoate 110 mcg 144 3.9 -1.77 -0.60 -0.93, -0.28 <0.001
  Placebo 144 3.9 -1.16
Perennial allergic rhinitis trial
  Fluticasone furoate 110 mcg 143 3.5 -1.41 -0.23 -0.59, 0.13 0.214
  Placebo 151 3.4 -1.18

Onset of action was evaluated by frequent instantaneous TNSS assessments after the first dose in the clinical trials in patients with seasonal allergic rhinitis and perennial allergic rhinitis. Onset of action was generally observed within 24 hours in patients with seasonal allergic rhinitis. In patients with perennial rhinitis, onset of action was observed after 4 days of treatment. Continued improvement in symptoms was observed over approximately 1 and 3 weeks in patients with seasonal or perennial allergic rhinitis, respectively.

Pediatric Patients Aged 2 to 11 Years

The efficacy and safety of VERAMYST Nasal Spray were evaluated in 1,112 children (633 boys and 479 girls), mean age of 8 years with seasonal or perennial allergic rhinitis in 2 controlled clinical trials. The pediatric patients were treated with VERAMYST Nasal Spray 55 or 110 mcg once daily for 2 to 12 weeks (n = 369 for each dose). The trials were similar in design to the trials conducted in adolescents and adults; however, the efficacy determination was made from patient- or parent/guardian-reported TNSS for children aged 6 to <12 years. Children treated with VERAMYST Nasal Spray generally exhibited greater decreases in nasal symptoms than placebo-treated patients. In seasonal allergic rhinitis, the difference in rTNSS was statistically significant only for the 110-mcg dose. In perennial allergic rhinitis, the difference in rTNSS was statistically significant only for the 55-mcg dose. Changes in rTOSS in the seasonal allergic rhinitis trial were not statistically significant compared with placebo for either dose. rTOSS was not assessed in the perennial allergic rhinitis trial. Table 5 displays the efficacy results from the clinical trials in patients with perennial allergic rhinitis and seasonal allergic rhinitis in children aged 6 to <12 years. Efficacy in children aged 2 to <6 years was supported by a numerical decrease in the rTNSS.

Table 5: Mean Changes in Efficacy Variables in Pediatric Patients Aged 6 to <12 Years With Seasonal or Perennial Allergic Rhinitis

Treatment n Baseline Change From Baseline – LS Mean Difference From Placebo
LS Mean 95% CI P Value
Reflective Total Nasal Symptom Scores
Seasonal allergic rhinitis trial
  Fluticasone furoate 55 mcg 151 8.6 -2.71 -0.16 -0.69, 0.37 0.553
  Fluticasone furoate 110 mcg 146 8.5 -3.16 -0.62 -1.15, -0.08 0.025
  Placebo 149 8.4 -2.54
Perennial allergic rhinitis trial
  Fluticasone furoate 55 mcg 144 8.5 -4.16 -0.75 -1.24, -0.27 0.003
  Fluticasone furoate 110 mcg   140 8.6 -3.86 -0.45 -0.95, 0.04 0.073
  Placebo 147 8.5 -3.41
Instantaneous Total Nasal Symptom Scores
Seasonal allergic rhinitis trial
  Fluticasone furoate 55 mcg 151 8.4 -2.37 -0.23 -0.77, 0.30 0.389
  Fluticasone furoate 110 mcg 146 8.3 -2.8 -0.67 -1.21, -0.13 0.015
  Placebo 149 8.4 -2.13
Perennial allergic rhinitis trial
  Fluticasone furoate 55 mcg 144 8.3 -3.62 -0.75 -1.24, -0.27 0.002
  Fluticasone furoate 110 mcg 140 8.3 -3.52 -0.65 -1.14, -0.16 0.009
  Placebo 147 8.3 -2.87
Reflective Total Ocular Symptom Scores
Seasonal allergic rhinitis trial
  Fluticasone furoate 55 mcg 151 4.4 -1.26 0.04 -0.33, 0.41 0.826
  Fluticasone furoate 110 mcg 146 4.1 -1.45
  Placebo 149 3.8 -1.3

Last reviewed on RxList: 10/10/2012
This monograph has been modified to include the generic and brand name in many instances.

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