Flonase

[Fluticasone]

"As-needed" use was prospectively defined as average use of study medication no more than 75% of study days. Average use of study medications was 57% to 70% of days for all treatment arms. The studies demonstrated significantly greater reduction in TNSS (sum of nasal congestion, rhinorrhea, sneezing, and nasal itching) with FLONASE Nasal Spray 200 mcg compared to placebo. The relative difference in efficacy with as-needed use as compared to regularly administered doses was not studied.

Three randomized, double-blind, parallel-group, vehicle placebo-controlled trials were conducted in 1,191 patients to investigate regular use of FLONASE Nasal Spray in patients with perennial nonallergic rhinitis. These trials evaluated the patient-rated TNSS (nasal obstruction, postnasal drip, rhinorrhea) in patients treated for 28 days of double-blind therapy and in 1 of the 3 trials for 6 months of open-label treatment. Two of these trials demonstrated that patients treated with FLONASE Nasal Spray at a dose of 100 mcg twice daily exhibited statistically significant decreases in TNSS compared with patients treated with vehicle.

Individualization of Dosage

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Patients should use FLONASE Nasal Spray at regular intervals for optimal effect.

Adult patients may be started on a 200-mcg once-daily regimen (two 50-mcg sprays in each nostril once daily). An alternative 200-mcg/ day dosage regimen can be given as 100 mcg twice daily (one 50-mcg spray in each nostril twice daily).

Individual patients will experience a variable time to onset and different degree of symptom relief. In 4 randomized, double-blind, vehicle placebo-controlled, parallel-group allergic rhinitis studies and 2 studies of patients in an outdoor "park" setting (park studies), a decrease in nasal symptoms in treated subjects compared to placebo was shown to occur as soon as 12 hours after treatment with a 200-mcg dose of FLONASE Nasal Spray. Maximum effect may take several days.

Regular-use patients who have responded may be able to be maintained (after 4 to 7 days) on 100 mcg/ day (1 spray in each nostril once daily). Some patients (12 years of age and older) with seasonal allergic rhinitis may find as-needed use of FLONASE Nasal Spray (not to exceed 200 mcg daily) effective for symptom control (see Clinical Trials). Greater symptom control may be achieved with scheduled regular use. Efficacy of as-needed use of FLONASE Nasal Spray has not been studied in pediatric patients under 12 years of age with seasonal allergic rhinitis, or patients with perennial allergic or nonallergic rhinitis.

Pediatric patients (4 years of age and older) should be started with 100 mcg (1 spray in each nostril once daily). Treatment with 200 mcg (2 sprays in each nostril once daily or 1 spray in each nostril twice daily) should be reserved for pediatric patients not adequately responding to 100 mcg daily. Once adequate control is achieved, the dosage should be decreased to 100 mcg (1 spray in each nostril) daily. Maximum total daily doses should not exceed 2 sprays in each nostril (total dose, 200 mcg/ day). There is no evidence that exceeding the recommended dose is more effective.

Drug Interactions

Fluticasone propionate is a substrate of cytochrome P450 3A4. A drug interaction study with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations
(see CLINICAL PHARMACOLOGY: Drug Interactions).

During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Therefore, coadministration of fluticasone propionate and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.

In a placebo-controlled, crossover study in 8 healthy volunteers, coadministration of a single dose of orally inhaled fluticasone propionate (1,000 mcg; 5 times the maximum daily intranasal dose) with multiple doses of ketoconazole (200 mg) to steady state resulted in increased plasma fluticasone propionate exposure, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol. Caution should be exercised when FLONASE Nasal Spray is coadministered with ketoconazole and other known potent cytochrome P450 3A4 inhibitors.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/ kg (approximately 20 times the maximum recommended daily intranasal dose in adults and approximately 10 times the maximum recommended daily intranasal dose in children on a mcg/ m 2 basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/ kg (approximately 2 times the maximum recommended daily intranasal dose in adults and approximately equivalent to the maximum recommended daily intranasal dose in children on a mcg/ m 2 basis) for 104 weeks. Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the mouse micronucleus test.

No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at subcutaneous doses up to 50 mcg/ kg (approximately 2 times the maximum recommended daily intranasal dose in adults on a mcg/ m 2 basis). Prostate weight was significantly reduced at a subcutaneous dose of 50 mcg/ kg.

Pregnancy:

Teratogenic Effects:

Pregnancy Category C.

Subcutaneous studies in the mouse and rat at 45 and 100 mcg/ kg, respectively (approximately equivalent to and 4 times the maximum recommended daily intranasal dose in adults on a mcg/ m 2 basis, respectively) revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. In the rabbit, fetal weight reduction and cleft palate were observed at a subcutaneous dose of 4 mcg/ kg (less than the maximum recommended daily intranasal dose in adults on a mcg/ m 2 basis). However, no teratogenic effects were reported at oral doses up to 300 mcg/ kg (approximately 25 times the maximum recommended daily intranasal dose in adults on a mcg/ m 2 basis) of fluticasone propionate to the rabbit. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration (see CLINICAL PHARMACOLOGY).

Fluticasone propionate crossed the placenta following oral administration of 100 mcg/ kg to rats or 300 mcg/ kg to rabbits (approximately 4 and 25 times, respectively, the maximum recommended daily intranasal dose in adults on a mcg/ m 2 basis).

There are no adequate and well-controlled studies in pregnant women. Fluticasone propionate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy.

Nursing Mothers

It is not known whether fluticasone propionate is excreted in human breast milk. However, other corticosteroids have been detected in human milk. Subcutaneous administration to lactating rats of 10 mcg/ kg of tritiated fluticasone propionate (less than the maximum recommended daily intranasal dose in adults on a mcg/ m 2 basis) resulted in measurable radioactivity in the milk. Since there are no data from controlled trials on the use of intranasal fluticasone propionate by nursing mothers, caution should be exercised when FLONASE Nasal Spray is administered to a nursing woman.

Pediatric Use

Six hundred fifty (650) patients aged 4 to 11 years and 440 patients aged 12 to 17 years were studied in US clinical trials with fluticasone propionate nasal spray. The safety and effectiveness of FLONASE Nasal Spray in children below 4 years of age 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 this reduction in growth velocity associated with intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for "catch-up" growth following discontinuation of treatment with intranasal corticosteroids has not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids, including FLONASE 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 FLONASE Nasal Spray, each patient should be titrated to the lowest dose that effectively controls his/ her symptoms.

A 1-year placebo-controlled clinical growth study was conducted in 150 pediatric patients (ages 3 to 9 years) to assess the effect of FLONASE Nasal Spray (single daily dose of 200 mcg, the maximum approved dose) on growth velocity. From the primary population of 56 patients receiving FLONASE Nasal Spray and 52 receiving placebo, the point estimate for growth velocity with FLONASE Nasal Spray was 0.14 cm/ year lower than that noted with placebo (95% confidence interval ranging from 0.54 cm/ year lower than placebo to 0.27 cm/ year higher than placebo). Thus, no statistically significant effect on growth was noted compared to placebo. No evidence of clinically relevant changes in HPA axis function or bone mineral density was observed as assessed by 12-hour urinary cortisol excretion and dual-energy x-ray absorptiometry, respectively.

The potential for FLONASE Nasal Spray to cause growth suppression in susceptible patients or when given at higher doses cannot be ruled out.

Geriatric Use

A limited number of patients 65 years of age and older (n = 129) or 75 years of age and older (n = 11) have been treated with FLONASE Nasal Spray in US and non-US clinical trials. While the number of patients is too small to permit separate analysis of efficacy and safety, the adverse reactions reported in this population were similar to those reported by younger patients.

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