Veramyst

Overdose

Chronic overdosage may result in signs/symptoms of hypercorticism. 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 trials (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 trials 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 price

Contraindications

VERAMYST Nasal Spray is contraindicated in patients with hypersensitivity to any of its ingredients.

Undesirable effects

Systemic and local corticosteroid use may result in the following:

• Epistaxis, ulcerations, Candida albicans infection, impaired wound healing, and nasal septal perforation
• Cataracts and glaucoma
• Immunosuppression
• Hypothalamic-pituitary-adrenal (HPA) axis effects, including growth reduction

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.

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

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.

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

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.

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.

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.

Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria.

Rhinalgia, nasal discomfort (including nasal burning, nasal irritation, and nasal soreness), nasal dryness, and nasal septal perforation.

Therapeutic indications

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.

Pharmacodynamic properties

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 trial and one 12-week safety and efficacy trial included assessments of 24-hour urinary cortisol excretion. Details of the trials and results are described below. In all 4 trials, 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 trial 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 trial conducted in children aged 2 to 11 years was of similar design to the adult trial, 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).

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 24hour 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.

A QT/QTc trial 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-controlled (a single dose of 400 mg oral moxifloxacin) cross-over trial. 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.

Pharmacokinetic properties

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 52week trial. 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. Trials 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.

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%.

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.

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.

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Fertility, pregnancy and lactation

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.

Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.

Qualitative and quantitative composition

VERAMYST Nasal Spray is a nasal spray suspension. Each spray (50 microliters) delivers 27.5 mcg of fluticasone furoate.

VERAMYST Nasal Spray, 27.5 mcg per spray, is supplied in a brown glass bottle enclosed in a nasal device with a nozzle and a mist-release button to actuate the spray in a box of 1 (NDC 0173-0753-00) with FDA-Approved Patient Labeling (see Patient Instructions for Use for proper actuation of the device). Each bottle contains a net fill weight of 10 g of white, liquid suspension and will provide 120 metered sprays. After priming , each spray delivers a fine mist containing 27.5 mcg of fluticasone furoate in 50 microliters of formulation through the nozzle. The contents of the bottle can be viewed through an indicator window. Shake the contents well before each use. The correct amount of medication in each spray cannot be assured before the initial priming and after 120 sprays have been used, even though the bottle is not completely empty. The nasal device should be discarded after 120 sprays have been used.

Store the device in the upright position with the cap in place between 15° and 30°C (59° and 86°F). Do not freeze or refrigerate.

GlaxoSmithKline, Research Triangle Park, NC 27709. Revised: May 2015

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

In clinical trials 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.

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.

Postmarketing cases of nasal septal perforation have been reported in patients following the intranasal application of VERAMYST Nasal Spray.

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.

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 (IOP), glaucoma, and/or cataracts.

Glaucoma and cataract formation was evaluated with intraocular pressure measurements and slit lamp examinations in 1 controlled 12-month trial in 806 adolescent and adult patients aged 12 years and older and in 1 controlled 12-week trial 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 trials. However, in the 12-month trial 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 trial, 7 patients (6 treated with VERAMYST Nasal Spray 110 mcg once daily and 1 patient treated with placebo) had cataracts identified during the trial that were not present at baseline.

Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria, may occur after administration of VERAMYST Nasal Spray. Discontinue VERAMYST Nasal Spray if such reactions occur.

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.

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.

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.

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.

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Inform patients that treatment with VERAMYST Nasal Spray may lead to adverse reactions, which include epistaxis and nasal ulceration. Candida infection may also occur with treatment with VERAMYST Nasal Spray. In addition, nasal corticosteroids are associated with nasal septal perforation and impaired wound healing. Advise patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma to not use VERAMYST Nasal Spray until healing has occurred.

Inform patients that glaucoma and cataracts are associated with nasal and inhaled corticosteroid use. Instruct patients to inform their healthcare providers if a change in vision is noted while using VERAMYST Nasal Spray.

Inform patients that hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria, may occur after administration of VERAMYST Nasal Spray. Instruct patients to discontinue use of VERAMYST Nasal Spray if such reactions occur.

Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their healthcare providers without delay. Inform patients of potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

Advise parents that VERAMYST Nasal Spray may slow growth in children. A child taking VERAMYST Nasal Spray should have his/her growth checked regularly.

Instruct patients to use VERAMYST Nasal Spray on a regular once-daily basis for optimal effect. VERAMYST Nasal Spray, like other corticosteroids, does not have an immediate effect on rhinitis symptoms. Although significant improvement is usually achieved within 24 hours in patients with seasonal allergic rhinitis and 4 days in patients with perennial allergic rhinitis, maximum benefit may not be reached for several days. Instruct the patient to not increase the prescribed dosage but contact the healthcare provider if symptoms do not improve or if the condition worsens.

Inform patients to avoid spraying VERAMYST Nasal Spray in their eyes.

Advise patients that coadministration of VERAMYST Nasal Spray and ritonavir is not recommended and to be cautious if coadministering with ketoconazole.

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).

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.

Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.

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.

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. The safety and effectiveness of VERAMYST Nasal Spray in children younger than 2 years have not been established.

Controlled clinical trials 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 “catchup” 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.

A randomized, double-blind, parallel-group, multicenter, 1-year placebo-controlled clinical growth trial evaluated the effect of 110 mcg of VERAMYST Nasal Spray once daily on growth velocity in 474 prepubescent children (girls aged 5 to 7.5 years and boys aged 5 to 8.5 years) with stadiometry. Mean growth velocity over the 52-week treatment period was lower in the patients receiving VERAMYST Nasal Spray (5.19 cm/year compared with placebo (5.46 cm/year). The mean treatment difference was -0.27 cm/year [95% CI: -0.48 to -0.06].

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.

Use VERAMYST Nasal Spray with caution in patients with moderate or severe hepatic impairment.

No dosage adjustment is required in patients with renal impairment.

Dosage (Posology) and method of 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.

Titrate an individual patient to the minimum effective dosage to reduce the possibility of side effects.

The recommended starting dosage is 110 mcg once daily administered as 2 sprays (27.5 mcg/spray) in each nostril. 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.

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, dosage reduction to 55 mcg once daily is recommended.

Interaction with other medicinal products and other forms of interaction

Systemic and local corticosteroid use may result in the following:

• Epistaxis, ulcerations, Candida albicans infection, impaired wound healing, and nasal septal perforation
• Cataracts and glaucoma
• Immunosuppression
• Hypothalamic-pituitary-adrenal (HPA) axis effects, including growth reduction

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.

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

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.

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

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.

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.

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.

Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria.

Rhinalgia, nasal discomfort (including nasal burning, nasal irritation, and nasal soreness), nasal dryness, and nasal septal perforation.

Fluticasone furoate is cleared by extensive first-pass metabolism mediated by CYP3A4. In a drug interaction trial 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 trial 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 trial should be carefully interpreted because the trial 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.