Treatment of Allergic Rhinitis
Veramyst® (fluticasone furoate) Nasal Spray is indicated for the treatment of the symptoms of seasonal and perennial allergic rhinitis in patients aged 2 years and older.
Veramyst Dosage and Administration
Administer Veramyst Nasal Spray by the intranasal route only. Prime Veramyst Nasal Spray before using for the first time by shaking the contents well and releasing 6 sprays into the air away from the face. When Veramyst Nasal Spray has not been used for more than 30 days or if the cap has been left off the bottle for 5 days or longer, prime the pump again until a fine mist appears. Shake Veramyst Nasal Spray well before each use.
Adults and Adolescents Aged 12 Years and Older
The recommended starting dosage is 110 mcg once daily administered as 2 sprays (27.5 mcg/spray) in each nostril. Titrate an individual patient to the minimum effective dosage to reduce the possibility of side effects. When the maximum benefit has been achieved and symptoms have been controlled, reducing the dosage to 55 mcg (1 spray in each nostril) once daily may be effective in maintaining control of allergic rhinitis symptoms.
Children Aged 2 to 11 Years
The recommended starting dosage in children is 55 mcg once daily administered as 1 spray (27.5 mcg/spray) in each nostril. Children not adequately responding to 55 mcg may use 110 mcg (2 sprays in each nostril) once daily. Once symptoms have been controlled, the dosage may be decreased to 55 mcg once daily.
Dosage Forms and Strengths
Veramyst Nasal Spray is a nasal spray suspension. Each spray (50 microliters) delivers 27.5 mcg of fluticasone furoate.
Contraindications
Veramyst Nasal Spray is contraindicated in patients with hypersensitivity to any of its ingredients [see Warnings and Precautions (5.3)].
Warnings and Precautions
Local Nasal Effects
Epistaxis and Nasal Ulceration: In clinical studies of 2 to 52 weeks’ duration, epistaxis and nasal ulcerations were observed more frequently and some epistaxis events were more severe in patients treated with Veramyst Nasal Spray than those who received placebo [see Adverse Reactions (6.1)].
Candida Infection: Evidence of localized infections of the nose with Candida albicans was seen on nasal exams in 7 of 2,745 patients treated with Veramyst Nasal Spray during clinical trials and was reported as an adverse event in 3 patients. When such an infection develops, it may require treatment with appropriate local therapy and discontinuation of Veramyst Nasal Spray. Therefore, patients using Veramyst Nasal Spray over several months or longer should be examined periodically for evidence of Candida infection or other signs of adverse effects on the nasal mucosa.
Nasal Septal Perforation: Postmarketing cases of nasal septal perforation have been reported in patients following the intranasal application of Veramyst Nasal Spray [see Adverse Reactions (6.2)].
Impaired Wound Healing: Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should not use Veramyst Nasal Spray 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 with intraocular pressure measurements and slit lamp examinations in 1 controlled 12-month study in 806 adolescent and adult patients aged 12 years and older and in 1 controlled 12-week study in 558 children aged 2 to 11 years. The patients had perennial allergic rhinitis and were treated with either Veramyst Nasal Spray (110 mcg once daily in adult and adolescent patients and 55 or 110 mcg once daily in pediatric patients) or placebo. Intraocular pressure remained within the normal range (<21 mmHg) in ≥98% of the patients in any treatment group in both studies. However, in the 12-month study in adolescents and adults, 12 patients, all treated with Veramyst Nasal Spray 110 mcg once daily, had intraocular pressure measurements that increased above normal levels (≥21 mmHg). In the same study, 7 patients (6 treated with Veramyst Nasal Spray 110 mcg once daily and 1 patient treated with placebo) had cataracts identified during the study that were not present at baseline.
Hypersensitivity Reactions, Including Anaphylaxis
Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria, may occur after administration of Veramyst Nasal Spray. Discontinue Veramyst Nasal Spray if such reactions occur [see Contraindications (4)].
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 children or adults who have not had these diseases or have not been 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 a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is 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 or measles develops, treatment with antiviral agents may be considered.
Corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract, untreated local or systemic fungal or bacterial infections, systemic viral or parasitic infections, or ocular herpes simplex because of the potential for worsening of these infections.
Hypothalamic-Pituitary-Adrenal Axis Effects
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 Veramyst Nasal Spray should be discontinued slowly, consistent with accepted procedures for discontinuing oral corticosteroid therapy.
The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency. In addition, some patients may experience symptoms of corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude, depression. Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress. In those patients who have asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, rapid decreases in systemic corticosteroid dosages may cause a severe exacerbation of their symptoms.
Use of Cytochrome P450 3A4 Inhibitors
Coadministration with ritonavir is not recommended because of the risk of systemic effects secondary to increased exposure to fluticasone furoate. Use caution with the coadministration of Veramyst Nasal Spray and other potent cytochrome P450 3A4(CYP3A4) inhibitors, such as ketoconazole [see Drug Interactions (7)].
Effect on Growth
Corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth routinely of pediatric patients receiving Veramyst Nasal Spray. To minimize the systemic effects of intranasal corticosteroids, including Veramyst Nasal Spray, titrate each patient’s dose to the lowest dosage that effectively controls his/her symptoms [see Use in Specific Populations (8.4)].
Adverse Reactions
Systemic and local corticosteroid use may result in the following:
- Epistaxis, ulcerations, Candida albicans infection, impaired wound healing, and nasal septal perforation [see Warnings and Precautions (5.1)]
- Cataracts and glaucoma [see Warnings and Precautions (5.2)]
- Immunosuppression [see Warnings and Precautions (5.4)]
- Hypothalamic-pituitary-adrenal (HPA) axis effects, including growth reduction [see Warnings and Precautions (5.5), Use in Specific Populations (8.4)]
Clinical Trials Experience
The safety data described below reflect exposure to Veramyst Nasal Spray in 1,563 patients with seasonal or perennial allergic rhinitis in 9 controlled clinical trials of 2 to 12 weeks’ duration. The data from adults and adolescents are based upon 6 clinical trials in which 768 patients with seasonal or perennial allergic rhinitis (473 females and 295 males aged 12 years and older) were treated with Veramyst Nasal Spray 110 mcg once daily for 2 to 6 weeks. The racial distribution of adult and adolescent patients receiving Veramyst Nasal Spray was 82% white, 5% black, and 13% other. The data from pediatric patients are based upon 3 clinical trials in which 795 children with seasonal or perennial rhinitis (352 females and 443 males aged 2 to 11 years) were treated with Veramyst Nasal Spray 55 or 110 mcg once daily for 2 to 12 weeks. The racial distribution of pediatric patients receiving Veramyst Nasal Spray was 75% white, 11% black, and 14% other.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adults and Adolescents Aged 12 Years and Older: Overall adverse reactions were reported with approximately the same frequency by patients treated with Veramyst Nasal Spray and those receiving placebo. Less than 3% of patients in clinical trials discontinued treatment because of adverse reactions. The rate of withdrawal among patients receiving Veramyst Nasal Spray was similar or lower than the rate among patients receiving placebo.
Table 1 displays the common adverse reactions (>1% in any patient group receiving Veramyst Nasal Spray) that occurred more frequently in patients aged 12 years and older treated with Veramyst Nasal Spray compared with placebo-treated patients.
Table 1. Adverse Reactions With >1% Incidence in Controlled Clinical Trials of 2 to 6 Weeks’ Duration With Veramyst Nasal Spray in Adult and Adolescent Patients With Seasonal or Perennial Allergic Rhinitis
Adverse Event
|
Adult and Adolescent Patients
Aged 12 Years and Older
|
Vehicle Placebo
(n = 774)
|
Veramyst Nasal Spray
110 mcg Once Daily
(n = 768)
|
|
Headache
|
54 (7%)
|
72 (9%)
|
Epistaxis
|
32 (4%)
|
45 (6%)
|
Pharyngolaryngeal pain
|
8 (1%)
|
15 (2%)
|
Nasal ulceration
|
3 (<1%)
|
11 (1%)
|
Back pain
|
7 (<1%)
|
9 (1%)
|
There were no differences in the incidence of adverse reactions based on gender or race. Clinical trials did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger subjects.
Pediatric Patients Aged 2 to 11 Years: In the 3 clinical trials in pediatric patients aged 2 to <12 years, overall adverse reactions were reported with approximately the same frequency by patients treated with Veramyst Nasal Spray and those receiving placebo. Table 2 displays the common adverse reactions (>3% in any patient group receiving Veramyst Nasal Spray), that occurred more frequently in patients aged 2 to 11 years treated with Veramyst Nasal Spray compared with placebo-treated patients.
Table 2. Adverse Reactions With >3% Incidence in Controlled Clinical Trials of 2 to 12 Weeks’ Duration With Veramyst Nasal Spray in Pediatric Patients With Seasonal or Perennial Allergic Rhinitis
Adverse Event
|
Pediatric Patients Aged 2 to <12 Years
|
Vehicle Placebo
(n = 429)
|
Veramyst Nasal Spray
55 mcg Once Daily
(n = 369)
|
Veramyst Nasal Spray
110 mcg Once Daily
(n = 426)
|
|
Headache
|
31 (7%)
|
28 (8%)
|
33 (8%)
|
Nasopharyngitis
|
21 (5%)
|
20 (5%)
|
21 (5%)
|
Epistaxis
|
19 (4%)
|
17 (5%)
|
17 (4%)
|
Pyrexia
|
7 (2%)
|
17 (5%)
|
19 (4%)
|
Pharyngolaryngeal pain
|
14 (3%)
|
16 (4%)
|
12 (3%)
|
Cough
|
12 (3%)
|
12 (3%)
|
16 (4%)
|
There were no differences in the incidence of adverse reactions based on gender or race. Pyrexia occurred more frequently in children aged 2 to <6 years compared with children aged 6 to <12 years.
Long-Term (52-Week) Safety Trial: In a 52-week, placebo-controlled, long-term safety trial, 605 patients (307 females and 298 males aged 12 years and older) with perennial allergic rhinitis were treated with Veramyst Nasal Spray 110 mcg once daily for 12 months and 201 were treated with placebo nasal spray. While most adverse reactions were similar in type and rate between the treatment groups, epistaxis occurred more frequently in patients who received Veramyst Nasal Spray (123/605, 20%) than in patients who received placebo (17/201, 8%). Epistaxis tended to be more severe in patients treated with Veramyst Nasal Spray. All 17 reports of epistaxis that occurred in patients who received placebo were of mild intensity, while 83, 39, and 1 of the total 123 epistaxis events in patients treated with Veramyst Nasal Spray were of mild, moderate, and severe intensity, respectively. No patient experienced a nasal septal perforation during this trial.
Postmarketing Experience
In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use of Veramyst Nasal Spray. 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. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to fluticasone furoate or a combination of these factors.
Immune System Disorders: Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria.
Respiratory, Thoracic, and Mediastinal Disorders: Rhinalgia, nasal discomfort (including nasal burning, nasal irritation, and nasal soreness), nasal dryness, and nasal septal perforation.
Drug Interactions
Fluticasone furoate is cleared by extensive first-pass metabolism mediated by CYP3A4. In a drug interaction study of intranasal fluticasone furoate and the CYP3A4 inhibitor ketoconazole given as a 200-mg once-daily dose for 7 days, 6 of 20 subjects receiving fluticasone furoate and ketoconazole had measurable but low levels of fluticasone furoate compared with 1 of 20 receiving fluticasone furoate and placebo. Based on this study and the low systemic exposure, there was a 5% reduction in 24-hour serum cortisol levels with ketoconazole compared with placebo. The data from this study should be carefully interpreted because the study was conducted with ketoconazole 200 mg once daily rather than 400 mg, which is the maximum recommended dosage. Therefore, caution is required with the coadministration of Veramyst Nasal Spray and ketoconazole or other potent CYP3A4 inhibitors.
Based on data with another glucocorticoid, fluticasone propionate, metabolized by CYP3A4, coadministration of Veramyst Nasal Spray with the potent CYP3A4 inhibitor ritonavir is not recommended because of the risk of systemic effects secondary to increased exposure to fluticasone furoate. High exposure to corticosteroids increases the potential for systemic side effects, such as cortisol suppression.
Enzyme induction and inhibition data suggest that fluticasone furoate is unlikely to significantly alter the cytochrome P450-mediated metabolism of other compounds at clinically relevant intranasal dosages.
USE IN SPECIFIC POPULATIONS
Pregnancy
Teratogenic Effects: Pregnancy Category C. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels.
There were no teratogenic effects in rats and rabbits at inhaled fluticasone furoate dosages of up to 91 and 8 mcg/kg/day, respectively (approximately 7 and 1 times, respectively, the maximum recommended daily intranasal dose in adults on a mcg/m2 basis). There was also no effect on pre- or post-natal development in rats treated with up to 27 mcg/kg/day by inhalation during gestation and lactation (approximately 2 times the maximum recommended daily intranasal dose in adults on a mcg/m2 basis).
There are no adequate and well-controlled studies in pregnant women. Veramyst Nasal Spray should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.
Nursing Mothers
It is not known whether fluticasone furoate is excreted in human breast milk. However, other corticosteroids have been detected in human milk. Since there are no data from controlled trials on the use of intranasal fluticasone furoate by nursing mothers, caution should be exercised when Veramyst Nasal Spray is administered to a nursing woman.
Pediatric Use
Controlled clinical trials with Veramyst Nasal Spray included 1,224 patients aged 2 to 11 years and 344 adolescent patients aged 12 to 17 years [see Clinical Studies (14)]. The safety and effectiveness of Veramyst Nasal Spray in children younger than 2 years have not been established.
Controlled clinical studies have shown that intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect has been 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 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 Veramyst Nasal Spray, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks/benefits of treatment alternatives. To minimize the systemic effects of intranasal corticosteroids, including Veramyst Nasal Spray, each patient’s dose should be titrated to the lowest dosage that effectively controls his/her symptoms.
The potential for Veramyst Nasal Spray to cause growth suppression in susceptible patients or when given at higher than recommended dosages cannot be ruled out.
Geriatric Use
Clinical studies of Veramyst Nasal Spray did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Hepatic Impairment
Use Veramyst Nasal Spray with caution in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].
Renal Impairment
No dosage adjustment is required in patients with renal impairment [see Clinical Pharmacology (12.3)].
Overdosage
Chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.4)]. There are no data on the effects of acute or chronic overdosage with Veramyst Nasal Spray. Because of low systemic bioavailability and an absence of acute drug-related systemic findings in clinical studies (with dosages of up to 440 mcg/day for 2 weeks [4 times the maximum recommended daily dose]), overdose is unlikely to require any therapy other than observation.
Intranasal administration of up to 2,640 mcg/day (24 times the recommended adult dose) of fluticasone furoate was administered to healthy human volunteers for 3 days. Single- and repeat-dose studies with orally inhaled fluticasone furoate doses of 50 to 4,000 mcg have shown decreased mean serum cortisol at doses of 500 mcg or higher. The oral median lethal dose in mice and rats was >2,000 mg/kg (approximately 74,000 and 147,000 times, respectively, the maximum recommended daily intranasal dose in adults and 52,000 and 105,000 times, respectively, the maximum recommended daily intranasal dose in children, on a mcg/m2 basis).
Acute overdosage with the intranasal dosage form is unlikely since 1 bottle of Veramyst Nasal Spray contains approximately 3 mg of fluticasone furoate, and the bioavailability of fluticasone furoate is <1% for 2.64 mg/day given intranasally and 1% for 2 mg/day given as an oral solution.
Veramyst Description
Fluticasone furoate, the active component of Veramyst Nasal Spray, is a synthetic fluorinated corticosteroid having the chemical name (6α,11β,16α,17α) - 6,9 - difluoro - 17 - {[(fluoro - methyl)thio]carbonyl} - 11 - hydroxy - 16 - methyl - 3 - oxoandrosta - 1,4 - dien - 17 - yl 2-furancarboxylate and the following chemical structure:
Fluticasone furoate is a white powder with a molecular weight of 538.6, and the empirical formula is C27H29F3O6S. It is practically insoluble in water.
Veramyst Nasal Spray is an aqueous suspension of micronized fluticasone furoate for topical administration to the nasal mucosa by means of a metering (50 microliters), atomizing spray pump. After initial priming [see Dosage and Administration (2)], each actuation delivers 27.5 mcg of fluticasone furoate in a volume of 50 microliters of nasal spray suspension. Veramyst Nasal Spray also contains 0.015% w/w benzalkonium chloride, dextrose anhydrous, edetate disodium, microcrystalline cellulose and carboxymethylcellulose sodium, polysorbate 80, and purified water. It has a pH of approximately 6.
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 Cmax (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.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Fluticasone furoate produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at doses of up to 9 and 19 mcg/kg/day, respectively (less than the maximum recommended daily intranasal dose in adults and children on a mcg/m2 basis).
Fluticasone furoate did not induce gene mutation in bacteria or chromosomal damage in a mammalian cell mutation test in mouse lymphoma L5178Y cells in vitro. There was also no evidence of genotoxicity in the in vivo micronucleus test in rats.
No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at inhaled fluticasone furoate doses of up to 24 and 91 mcg/kg/day, respectively (approximately 2 and 7 times, respectively, the maximum recommended daily intranasal dose in adults on a mcg/m2 basis).
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
|
|
