Fluticasone Propionate Nasal Spray, USP, 50 MCG

Fluticasone propionate is a synthetic, trifluorinated corticosteroid with anti-inflammatory activity. In vitro dose response studies on a cloned human glucocorticoid receptor system involving binding and gene expression afforded 50% responses at 1.25 and 0.17 nM concentrations, respectively. Fluticasone propionate was 3-fold to 5-fold more potent than dexamethasone in these assays. Data from the McKenzie vasoconstrictor assay in man also support its potent glucocorticoid activity.

In preclinical studies, fluticasone propionate revealed progesterone-like activity similar to the natural hormone. However, the clinical significance of these findings in relation to the low plasma levels (see ) is not known. Pharmacokinetics

The precise mechanism through which fluticasone propionate affects allergic rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation. In 7 trials in adults, Fluticasone Propionate Nasal Spray,USP, has decreased nasal mucosal eosinophils in 66% (35% for placebo) of patients and basophils in 39% (28% for placebo) of patients. The direct relationship of these finding to long-term symptom relief is not known.

Fluticasone Propionate Nasal Spray, USP, like other corticosteroids, is an agent that does not have an immediate effect on allergic symptoms. A decrease in nasal symptoms has been noted in some patients 12 hours after initial treatment with Fluticasone Propionate Nasal Spray, USP. Maximum benefit may not be reached for several days. Similarly, when corticosteroids are discontinued, symptoms may not return for several days.

Fluticasone Propionate Nasal Spray, USP, was not studied in any special populations, and no gender-specific pharmacokinetic data have been obtained.

Fluticasone propionate is a substrate of cytochrome P450 3A4. Coadministration of fluticasone propionate and the highly potent cytochrome P450 3A4 inhibitor ritonavir is not recommended based upon a multiple- dose, crossover drug interaction study in 18 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous nasal spray alone were undetectable (<10 pg/mL) in most subjects, and when concentrations were detectable, peak levels (C ) averaged 11.9 pg/mL (range, 10.8 to 14.1 pg/mL) and AUC averaged 8.43 pg•hr/mL (range, 4.2 to 18.8 pg•hr/mL). Fluticasone propionate C and AUC increased to 318 pg/mL (range, 110 to 648 pg/mL) and 3,102.6 pg•hr/mL (range, 1,207.1 to 5,662.0 pg•hr/mL), respectively, after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in plasma cortisol area under the plasma concentration versus time curve (AUC). _{max (0-t) max (0-t)}

Caution should be exercised when other potent cytochrome P450 3A4 inhibitors are coadministered with fluticasone propionate. In a drug interaction study, coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in increased fluticasone propionate exposure and reduced plasma cortisol AUC, but had no effect on urinary excretion of cortisol.

In another multiple-dose drug interaction study, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics.

In a trial to evaluate the potential systemic and topical effects of Fluticasone Propionate Nasal Spray, USP, on allergic rhinitis symptoms, the benefits of comparable drug blood levels produced by Fluticasone Propionate Nasal Spray, USP, and oral fluticasone propionate were compared. The dosages used were 200 mcg of Fluticasone Propionate Nasal Spray, USP, the nasal spray vehicle (plus oral placebo), and 5 and 10 mg of oral fluticasone propionate (plus nasal spray vehicle) per day for 14 days. Plasma levels were undetectable in the majority of patients after intranasal dosing, but present at low levels in the majority after oral dosing. Fluticasone Propionate Nasal Spray, USP, was significantly more effective in reducing symptoms of allergic rhinitis than either the oral fluticasone propionate or the nasal vehicle. This trial demonstrated that the therapeutic effect of Fluticasone Propionate Nasal Spray, USP, can be attributed to the topical effects of fluticasone propionate.

In another trial, the potential systemic effects of Fluticasone Propionate Nasal Spray, USP, on the hypothalamic-pituitaryadrenal (HPA) axis were also studied in allergic patients. Fluticasone Propionate Nasal Spray, USP, given as 200 mcg once daily or 400 mcg twice daily was compared with placebo or oral prednisone 7.5 or 15 mg given in the morning. Fluticasone Propionate Nasal Spray, USP, at either dosage for 4 weeks did not affect the adrenal response to 6-hour cosyntropin stimulation, while both dosages of oral prednisone significantly reduced the response to cosyntropin.

Patients should use Fluticasone Propionate Nasal Spray, USP, 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, doubleblind, 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 Fluticasone Propionate Nasal Spray, USP. 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 Fluticasone Propionate Nasal Spray, USP (not to exceed 200 mcg daily) effective for symptom control (see ). Greater symptom control may be achieved with scheduled regular use. Efficacy of asneeded use of Fluticasone Propionate Nasal Spray, USP, has not been studied in pediatric patients under 12 years of age with seasonal allergic rhinitis, or patients with perennial allergic or nonallergic rhinitis. CLINICAL TRIALS

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.

Intranasal corticosteroids may cause a reduction in growth velocity when administered to pediatric patients (see ). Rarely, immediate hypersensitivity reactions or contact dermatitis may occur after the administration of Fluticasone Propionate Nasal Spray, USP. Rare instances of wheezing, nasal septum perforation, cataracts, glaucoma, and increased intraocular pressure have been reported following the intranasal application of corticosteroids, including fluticasone propionate. PRECAUTIONS: Pediatric use

Use of excessive doses of corticosteroids may lead to signs or symptoms of hypercorticism and/or suppression of HPA function.

Although systemic effects have been minimal with recommended doses of Fluticasone Propionate Nasal Spray, USP, potential risk increases with larger doses. Therefore, larger than recommended doses of Fluticasone Propionate Nasal Spray, USP, should be avoided.

When used at higher than recommended doses or in rare individuals at recommended doses, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of Fluticasone Propionate Nasal Spray, USP, should be discontinued slowly consistent with accepted procedures for discontinuing oral corticosteroid therapy.

In clinical studies with fluticasone propionate administered intranasally, the development of localized infections of the nose and pharynx with albicans has occurred only rarely. When such an infection develops, it may require treatment with appropriate local therapy and discontinuation of treatment with Fluticasone Propionate Nasal Spray, USP. Patients using Fluticasone Propionate Nasal Spray, USP, over several months or longer should be examined periodically for evidence of Candida infection or other signs of adverse effects on the nasal mucosa. Candida

Intranasal 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 inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal septal ulcers, nasal surgery, or nasal trauma should not use a nasal corticosteroid until healing has occurred.

Patients being treated with Fluticasone Propionate Nasal Spray, USP, should receive the following information and instructions. This information is intended to aid them in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

Patients should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay.

Patients should use Fluticasone Propionate Nasal Spray, USP, at regular intervals for optimal effect. Some patients (12 years of age and older) with seasonal allergic rhinitis may find as-needed use of 200 mcg once daily effective for symptom control (see ). CLINICAL TRIALS

A decrease in nasal symptoms may occur as soon as 12 hours after starting therapy with Fluticasone Propionate Nasal Spray, USP. Results in several clinical trials indicate statistically significant improvement within the first day or two of treatment; however, the full benefit of Fluticasone Propionate Nasal Spray, USP, may not be achieved until treatment has been administered for several days. The patient should not increase the prescribed dosage but should contact the physician if symptoms do not improve or if the condition worsens.

For the proper use of Fluticasone Propionate Nasal Spray, USP, and to attain maximum improvement, the patient should read and follow carefully the patient’s instructions accompanying the product.

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 ). 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. CLINICAL PHARMACOLOGY: Drug Interactions

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 Fluticasone Propionate Nasal Spray, USP, is coadministered with ketoconazole and other known potent cytochrome P450 3A4 inhibitors.

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 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 basis) for 104 weeks. ^{2 2}

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 basis). Prostate weight was significantly reduced at a subcutaneous dose of 50 mcg/kg. ²

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 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 Fluticasone Propionate Nasal Spray, USP, is administered to a nursing woman. ²

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, USP. The safety and effectiveness of Fluticasone Propionate Nasal Spray, USP, 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 Fluticasone Propionate Nasal Spray, USP, 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 Fluticasone Propionate Nasal Spray, USP, 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 Fluticasone Propionate Nasal Spray, USP (single daily dose of 200 mcg, the maximum approved dose) on growth velocity. From the primary population of 56 patients receiving Fluticasone Propionate Nasal Spray, USP and 52 receiving placebo, the point estimate for growth velocity with Fluticasone Propionate Nasal Spray, USP 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 Fluticasone Propionate Nasal Spray, USP, to cause growth suppression in susceptible patients or when given at higher doses cannot be ruled out.

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 Fluticasone Propionate Nasal Spray, USP, 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.

Practice: In addition to adverse events reported from clinical trials, the following events have been identified during postapproval use of intranasal fluticasone propionate in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to fluticasone propionate or a combination of these factors.

The recommended starting dosage in is 2 sprays (50 mcg of fluticasone propionate each) in each nostril once daily (total daily dose, 200 mcg). The same dosage divided into 100 mcg given twice daily (e.g., 8 a.m. and 8 p.m.) is also effective. After the first few days, patients may be able to reduce their dosage to 100 mcg (1 spray in each nostril) once daily for maintenance therapy. Some patients (12 years of age and older) with seasonal allergic rhinitis may find as-needed use of 200 mcg once daily effective for symptom control (see ). Greater symptom control may be achieved with scheduled regular use. adults CLINICAL TRIALS

Patients should be started with 100 mcg (1 spray in each nostril once daily). Patients not adequately responding to 100 mcg may use 200 mcg (2 sprays in each nostril). Once adequate control is achieved, the dosage should be decreased to 100 mcg (1 spray in each nostril) daily.

The maximum total daily dosage should not exceed 2 sprays in each nostril (200 mcg/day). (See ). CLINICAL TRIALS: Individualization of Dosage

Fluticasone Propionate Nasal Spray, USP, is not recommended for children under 4 years of age.

Illustrated patient’s instructions for proper use accompany each package of Fluticasone Propionate Nasal Spray, USP.

Rhinitis is a word that means inflammation of the lining of the nose. If you suffer from rhinitis, your nose becomes stuffy and runny. Rhinitis can also make your nose itchy, and you may sneeze a lot. Rhinitis can be caused by allergies to pollen, animals, molds, or other materials-or it may have a nonallergic cause.

Your doctor has prescribed Fluticasone Propionate Nasal Spray, USP, a medicine that can help treat your rhinitis. Fluticasone Propionate Nasal Spray, USP, contains fluticasone propionate, which is a synthetic corticosteroid. Corticosteroids are natural substances found in the body that help fight inflammation. When you spray Fluticasone Propionate Nasal Spray, USP, into your nose, it helps to reduce the symptoms of allergic reactions and the stuffiness, runniness, itching, and sneezing that can bother you.

1. Shake gently before using.

2. Use your nasal spray as directed by your doctor. The directions are on the pharmacy label.

3. Keep your nasal spray . out of the reach of children

• If you are pregnant (or intending to become pregnant),
• If you are breastfeeding a baby,
• If you are allergic to Fluticasone Propionate Nasal Spray, USP, or any other nasal corticosteroid,
• If you are taking a medicine containing ritonavir (commonly used to treat HIV infection or AIDS).

In some circumstances, this medicine may not be suitable and your doctor may wish to give you a different medicine. Make sure that your doctor knows what other medicines you are taking. TELL YOUR DOCTOR BEFORE STARTING TO TAKE THIS MEDICINE.

• Follow the instructions shown in the rest of this leaflet. If you have any problems, tell your doctor or pharmacist.
• It is important that you use it as directed by your doctor. The pharmacist¡¦s label will usually tell you what dose to take and how often. If it doesn¡¦t, or you are not sure, ask your doctor or pharmacist.

• For , the usual starting dose is . Sometimes your doctor may recommend using 1 spray in each nostril twice a day (morning and evening). You should not use more than a total of 2 sprays in each nostril daily. After you have begun to feel better, 1 spray in each nostril daily may be adequate for you. ADULTS 2 sprays in each nostril once daily

  For (4 years of age and older), the usual starting dosage is . Sometimes your doctor may recommend using 2 sprays in each nostril daily. Then, after you have begun to feel better, 1 spray in each nostril daily may be adequate for you. ADOLESCENTS and CHILDREN 1 spray in each nostril once daily

• DO NOT use more of your medicine or take it more often than your doctor advises.
• Fluticasone Propionate Nasal Spray, USP, may begin to work within 12 hours of the first dose, but it takes several days of regular use to reach its greatest effect. It is important that you use Fluticasone Propionate Nasal Spray, USP, as prescribed by your doctor. Best results will be obtained by using the spray on a regular basis. If symptoms disappear, contact your doctor for further instructions.
• If you also have itchy, watery eyes, you should tell your doctor. You may be given an additional medicine to treat your eyes. Be careful not to confuse them, particularly if the second medicine is an eye drop.
• If you miss a dose, just take your regularly scheduled next dose when it is due. DO NOT DOUBLE the dose.

Read the complete instructions carefully and use only as directed.

Your nasal spray should be cleaned at least once a week. To do this:

1. Remove the cap and then gently pull upwards to free the nasal applicator.

2. Wash the applicator and cap under warm tap water. Allow to dry at room temperature, then place the applicator and cap back on the bottle.

3. If the nasal applicator becomes blocked, it can be removed as above and left to soak in warm water. Rinse with cold tap water, dry, and refit. Do not try to unblock the nasal applicator by inserting a pin or other sharp object.

• Keep your Fluticasone Propionate Nasal Spray, USP, . out of the reach of children
• Avoid spraying in eyes.
• Store between 4° and 30°C (39°F and 86°F).
• Do not use your Fluticasone Propionate Nasal Spray, USP, after the expiration date shown on the label and box.

REMEMBER: This medicine has been prescribed for you by your doctor. DO NOT give this medicine to anyone else.

The leaflet does not contain the complete information about your medicine. . If you have any questions, or are not sure about something, then you should ask your doctor or pharmacist

You may want to read this leaflet again. Please DO NOT THROW IT AWAY until you have finished your medicine.

To report SUSPECTED ADVERSE REACTIONS, contact Hi-Tech Pharmacal Co., Inc. at 1-800-262-9010 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Manufactured by:

Hi-Tech Pharmacal Co., Inc.

Amityville, N.Y. 11701

Made in U.S.A.

Rev. 700:05 8/11