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fluticasone prop 50 mcg spray

In stock Manufacturer APOTEX CORP 60505082901
$16.96 / 16 Grams Aer W/adap

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Uses

Fluticasone propionate nasal spray is used for symptomatic treatment of seasonal or perennial allergic rhinitis and also for perennial nonallergic rhinitis.

Allergic Rhinitis

Fluticasone propionate nasal spray is used for the symptomatic treatment of seasonal or perennial allergic rhinitis.

In patients with seasonal or perennial allergic rhinitis, intranasal administration of fluticasone propionate generally provides symptomatic relief of watery rhinorrhea, nasal congestion, sneezing, postnasal drip, and nasal itching. Although intranasal fluticasone propionate generally does not relieve manifestations of conjunctivitis, improvement in ophthalmic manifestations has occurred in some patients receiving the drug intranasally. Since fluticasone propionate is thought to exert a local effect on the nasal mucosa, the mechanism for these ophthalmic effects is not fully understood. Improvement in ophthalmic manifestations may be caused partly by a decrease in the nasolacrimal reflex, which occurs as symptoms of rhinitis improve. It also has been suggested that decreased edema of the nasal mucosa may promote better drainage of tears through the lacrimal ducts.

Evidence from a limited number of studies in children 4-11 years of age suggests that intranasal fluticasone propionate 100-200 mcg daily is more effective than placebo in relieving symptoms of seasonal allergic rhinitis and is not associated with unusual adverse effects compared with those observed in adults receiving the drug; however, in one study in children, improvement in nasal symptoms with intranasal fluticasone propionate therapy was less pronounced than that generally reported in adults.

Intranasal fluticasone propionate (200 mcg daily given in 1 or 2 divided doses in adults and adolescents) appears to be at least as effective as intranasal beclomethasone dipropionate (168 mcg twice daily) in the treatment of seasonal or perennial allergic rhinitis; preliminary data also suggest efficacy comparable to that of usual dosages of intranasal flunisolide acetonide. In children 6-11 years of age with perennial allergic rhinitis, intranasal fluticasone propionate (100 mcg once or twice daily) was as effective as intranasal beclomethasone dipropionate (168 mcg twice daily). In a limited number of studies, fluticasone propionate generally was more effective in relieving nasal symptoms in adults and adolescents than the oral antihistamines terfenadine (no longer commercially available in the US), astemizole (no longer commercially available in the US), cetirizine, or loratadine or the mast-cell inhibitor cromolyn sodium. However, in a randomized, controlled study in patients with seasonal allergic rhinitis, addition of oral cetirizine (10 mg once daily) to the usual dosage of fluticasone propionate (200 mcg once daily) did not improve control of nasal and ocular symptoms compared with fluticasone propionate therapy alone. Whether the very low oral bioavailability of intranasal fluticasone propionate (see Pharmacokinetics) will be associated with a reduced risk of systemic adverse effects compared with other currently available intranasal corticosteroids remains to be established. Current evidence suggests that 200 mcg of fluticasone propionate given once daily is as effective as 100 mcg of the drug given twice daily.

In several dose-response studies in pediatric patients, once-daily administration of 100 mcg of fluticasone propionate appeared to be as effective as 200 mcg once daily; however, pediatric patients with more severe symptoms of allergic rhinitis benefited from the higher recommended dosage (200 mcg daily).

In 2 double-blind, placebo (vehicle)-controlled, short-term (28-day) trials in patients 12 years of age and older with seasonal allergic rhinitis, patients using fluticasone (up to 200 mcg [2 sprays in each nostril] once daily) on an as-needed basis experienced a greater reduction in symptoms (nasal congestion, rhinorrhea, sneezing, and nasal pruritus) than patients receiving placebo. Study medication was used an average of 57-70% of study days for all treatment groups; the relative difference in efficacy with as-needed use compared with regularly scheduled use of fluticasone was not studied. Efficacy of as-needed fluticasone has not been studied in patients younger than 12 years of age with seasonal allergic rhinitis or in patients with perennial allergic or nonallergic rhinitis.

In patients with seasonal or perennial allergic rhinitis, symptomatic relief usually is evident within 12-48 hours of continuous intranasal fluticasone propionate therapy; however, up to 2-4 days may be required for optimum effectiveness in some patients. Supplemental therapy with oral antihistamines and/or topical nasal decongestants may be necessary until an acceptable clinical response is achieved. In some patients, ophthalmic preparations may be necessary to relieve manifestations of conjunctivitis not controlled by intranasal corticosteroids. Although ophthalmic preparations containing vasoconstrictors and antihistamines or corticosteroids may be effective in relieving ophthalmic inflammatory symptoms in patients with rhinitis, concurrent use of ophthalmic and intranasal corticosteroids generally is not recommended since the risk of adverse ophthalmic effects associated with corticosteroid therapy (e.g., glaucoma, cataract formation, exacerbation of ophthalmic infections) may be increased. In some patients with seasonal or perennial rhinitis, especially those with concurrent asthmatic conditions, continuous concomitant therapies (e.g., oral or orally inhaled corticosteroids, bronchodilators, antihistamines, decongestants) may be required for optimum symptomatic relief; concomitant therapy with intranasal and other systemic corticosteroids may increase the risk of hypercorticism and/or HPA-axis suppression.(See Cautions: Precautions and Contraindications.)

Nonallergic Rhinitis

Fluticasone propionate nasal spray is used for the symptomatic treatment of perennial nonallergic rhinitis. Evidence from the majority of placebo (vehicle)-controlled studies in patients with nonallergic rhinitis indicates that intranasal administration of fluticasone propionate is associated with lower total nasal symptom scores (nasal obstruction, postnasal drip, rhinorrhea) than administration of vehicle.

Fluticasone propionate has been used successfully prior to the onset of the pollen season for the prophylaxis of symptoms of seasonal allergic rhinitis. In a comparative study, fluticasone propionate (200 mcg once daily) appeared to be more effective than cromolyn sodium (5.2 mg 4 times daily) in preventing nasal symptoms (e.g., sneezing, rhinorrhea, nasal congestion or itching) when the drugs were initiated at least 1 week prior to the anticipated start of the grass pollen season in patients with seasonal allergic rhinitis; both treatments were well tolerated. Fluticasone propionate has been used successfully by oral inhalation in the management of asthma in patients whose symptoms were not controlled by occasional use of bronchodilators.

Dosage and Administration

Administration

Fluticasone propionate is administered by nasal inhalation using a metered-dose nasal spray pump. Patients should be instructed carefully in the use of the nasal spray pump, including the need to prime the pump prior to first use or after a period of nonuse (i.e., 1 week or more). To obtain optimum results, patients also should be given a copy of the patient instructions provided by the manufacturer.

Prior to administration of fluticasone propionate nasal spray, patients should clear their nasal passages; administration of a topical nasal decongestant about 5-15 minutes before intranasal corticosteroid administration may be useful during the first 2 or 3 days of therapy in patients with blocked nasal passages to ensure adequate penetration of the drug. Prior to initial use, the nasal inhaler must be primed. Patients should tilt the head slightly forward, insert the nasal adapter into one nostril, and point the tip of the adapter toward the inflamed nasal turbinates and away from the nasal septum. For maximum therapeutic effect and to ensure adequate penetration of the drug, patients should pump the drug into one nostril while holding the other nostril closed and should concurrently inspire through the nose. This procedure is then repeated for the other nostril. If sneezing occurs during drug administration, patients should wait until sneezing has stopped, then clear the nasal passages and repeat administration of the dose.

The manufacturer recommends cleaning of the nasal spray adapter and/or pump at least once weekly. After removing the nasal adapter and dust cap, these pieces should be rinsed in warm water and dried thoroughly. If the nasal adapter becomes clogged, the piece should be soaked in warm water; cleaning by inserting a sharp object into the piece is not recommended.

Dosage

The nasal inhaler delivers about 50 mcg of fluticasone propionate per metered spray. The commercially available preparation delivers about 120 metered sprays per 16-g bottle; the container should be discarded after the labeled number of actuations have been used since the correct dose per inhalation cannot be assured if used for additional doses. Dosage of intranasal fluticasone propionate should be adjusted according to individual requirements and response; the lowest effective dosage should be used in order to minimize potential systemic effects of the drug.(See Cautions: Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression.) The maximum daily dosage of intranasal fluticasone propionate should not exceed 100 mcg in each nostril (total of 200 mcg daily).

Rhinitis

For the symptomatic treatment of seasonal or perennial allergic rhinitis or perennial nonallergic rhinitis, the usual initial adult dosage of fluticasone propionate nasal spray is 100 mcg (2 sprays) in each nostril once daily (200 mcg total daily dosage). This dosage of fluticasone propionate also may be administered as 50 mcg (1 spray) in each nostril twice daily (e.g., at 8 am and 8 pm).

Some patients 12 years of age and older with seasonal allergic rhinitis may find as-needed use of fluticasone propionate to be effective in controlling symptoms at a dosage of 100 mcg (2 sprays) in each nostril once daily (200 mcg total daily dosage). However, the manufacturer states that optimal symptom control may be achieved with regularly scheduled use of fluticasone. If the once-daily regimen is used, some clinicians recommend administration of fluticasone propionate in the morning.

In adolescents and children 4 years of age or older, the usual initial dosage of fluticasone propionate is 50 mcg (1 spray) in each nostril daily (100 mcg total daily dosage). Patients not responding adequately to the 100-mcg daily dosage or those with more severe symptoms may use 100 mcg (2 sprays) in each nostril daily (200 mcg total daily dosage).

In patients with seasonal or perennial allergic rhinitis or nonallergic rhinitis, the onset of symptomatic relief may occur within 12-48 hours of initiation of intranasal fluticasone propionate therapy in adults and within 36 hours in children; however, up to 2-4 days generally is required for optimum effectiveness in most patients. There is no evidence that higher than recommended dosages or increased frequency of administration of intranasal fluticasone propionate is beneficial; exceeding the maximum recommended daily dosage may increase the risk of adverse systemic effects (e.g., HPA-axis suppression, Cushing's syndrome).(See Cautions: Precautions and Contraindications.) Patients should be instructed to contact their clinician during intranasal fluticasone propionate therapy if manifestations of the condition do not improve or if the condition worsens.

Once the manifestations of seasonal or perennial allergic rhinitis or nonallergic rhinitis have been controlled, dosage of fluticasone propionate should be reduced gradually to the lowest effective level. Adults who have responded to an initial fluticasone propionate dosage of 200 mcg (2 sprays in each nostril) daily after a few days may be able to reduce their dosage to 100 mcg (1 spray in each nostril) daily for maintenance therapy. In pediatric patients with more severe symptoms of perennial or seasonal allergic rhinitis requiring the maximum dosage for control of symptoms (200 mcg daily), dosage should be reduced to 100 mcg (1 spray in each nostril) daily once adequate control of symptoms is achieved.

Cautions

Intranasal fluticasone propionate generally is well tolerated. Adverse effects with intranasal fluticasone propionate therapy usually are mild and local and resolve without specific treatment. The manufacturer states that systemic corticosteroid effects were not reported with fluticasone nasal spray in controlled trials of up to 6 months' duration, but systemic effects (e.g., growth suppression) have been reported with intranasal corticosteroids, including fluticasone propionate, during postmarketing experience.(See Cautions: Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression.) In clinical studies with fluticasone propionate, adverse effects required discontinuance of the drug in less than 2% of patients; this discontinuance rate was similar in patients receiving active drug or placebo (e.g., vehicle). Because some adverse effects of intranasal fluticasone propionate therapy may mimic symptoms of rhinitis (e.g., nasal congestion, nasal discharge, sinusitis, rhinorrhea), it may be difficult to distinguish drug-induced adverse effects from the underlying disease process. In some placebo-controlled and/or comparative studies, the incidence of adverse effects in patients receiving intranasal fluticasone propionate therapy was similar to that in patients receiving placebo or other active drug (e.g., oral terfenadine [no longer commercially available in the US], intranasal beclomethasone dipropionate). In adults and children with seasonal allergic rhinitis who received 50-1600 mcg of intranasal fluticasone propionate daily in 1 or 2 divided doses for 14-28 days, the incidence of adverse effects did not appear to be dose related.

Nasopharyngeal or Respiratory Effects

The most frequent adverse effects of fluticasone propionate nasal spray involve the nasal mucous membranes. Epistaxis or sensations of nasal burning/irritation have been reported in 6-6.9 or 2.4-3.2%, respectively, of patients receiving fluticasone propionate (100-200 mcg once daily) in controlled studies. These adverse effects usually are of short duration and rarely require changes in or discontinuance of therapy. Sensations of nasal burning may result from excipients in the commercially available preparation since the frequency and severity of these effects are similar in patients receiving an intranasal placebo vehicle with identical inactive ingredients. In addition, the similar occurrence of adverse nasal effects in fluticasone propionate- or placebo-treated patients with seasonal or perennial rhinitis may result from physical contact and irritation of the characteristically sensitive nasal passages of these patients. Pharyngitis or cough has been reported in 6-7.8 or 3.6-3.8%, respectively, of patients receiving the drug. Symptoms of asthma have occurred in 7.2 or 3.3% of those receiving 100 or 200 mcg, respectively, of fluticasone propionate once daily.

Other adverse nasopharyngeal or respiratory effects occurring in 1-3% of patients receiving fluticasone propionate nasal spray include nasal secretions containing blood, nasal discharge, and bronchitis. Sneezing, rhinorrhea, sinusitis, sore throat, throat irritation and dryness, hoarseness, voice changes, alteration or loss of sense of taste and/or smell, nasal congestion or blockage, or nasal dryness has been reported in patients receiving fluticasone propionate nasal spray in controlled studies or during postmarketing surveillance. Nasal septum excoriation, ulceration, or nasal septum crusting also has been reported in patients receiving fluticasone propionate nasal spray. It has been suggested that nasal septum crusting, nasal dryness accompanied by nasal manipulation (''picking''), or nasal bleeding may predispose to the development of nasal perforation, which has been reported rarely with intranasal administration of corticosteroids, including fluticasone propionate. In 2 patients who experienced nasal perforation with fluticasone propionate, both had previous septal surgery that may have increased the risk of nasal perforation.

Localized candidal infections of the nose and/or pharynx have occurred rarely during fluticasone propionate therapy. If a candidal infection is suspected, appropriate local anti-infective therapy and/or discontinuance of intranasal corticosteroid therapy should be considered. Upper respiratory infection also has been reported with intranasal fluticasone propionate therapy, but a causal relationship to the drug has not been established.

Although not reported to date in patients receiving fluticasone propionate or other intranasal corticosteroids, some clinicians caution that atrophic rhinitis potentially could develop during chronic therapy with an intranasal corticosteroid, since atrophic dermatitis has occurred in patients treated with topical corticosteroids to the skin for prolonged periods. However, the theoretical potential for nasal atrophy is thought to be less than that for atrophic dermatitis because of the smaller residence time of the intranasal corticosteroid on the nasal mucosa compared with that of topical corticosteroids on the skin. Rhinoscopic assessment or nasal examination of patients with rhinitis treated continuously with intranasal fluticasone propionate for 6-12 months has shown no evidence of serious mucosal damage.

Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression

Adrenal suppression, based on mean plasma cortisol, morning plasma cortisol, or urinary 17-ketogenic steroid (17-KS) determinations, has not been observed to date when fluticasone propionate was administered intranasally in adults receiving 200 mcg daily for up to 12 months or in children (aged 4-11 years) receiving intranasal fluticasone spray 100-200 mcg daily for 2-4 weeks. In addition, no evidence of growth suppression was noted in a 1-year, placebo-controlled study in children 3-9 years of age receiving fluticasone propionate 200 mcg once daily.(See Cautions: Pediatric Precautions.)However, growth suppression has been reported during other controlled clinical trials in children receiving intranasal corticosteroids, in the absence of laboratory evidence of HPA-axis suppression. This finding suggests that growth velocity may be a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA-axis function. While no clinically important alterations in plasma cortisol were observed in patients with asthma receiving orally inhaled fluticasone propionate dosages of 200-1500 mcg daily for up to 1 year, a relationship between plasma fluticasone propionate concentrations and inhibitory effects on stimulated cortisol production has been demonstrated after 4 weeks of treatment with fluticasone propionate inhalation aerosol. When administered orally (formulation currently not commercially available in the US) in single doses of up to 16 mg in healthy adults, fluticasone propionate did not appreciably affect plasma cortisol concentrations. However, evidence of HPA-axis suppression has been observed with oral fluticasone propionate therapy (20 mg daily) in several patients with distal ulcerative colitis or celiac disease; some of these patients had abnormal baseline ACTH-stimulated cortisol responses. In healthy males receiving oral fluticasone propionate (formulation currently not commercially available in the US) 10-20 mg 4 times daily for 10 days, mean plasma and urinary cortisol concentrations were reduced; approximately 11% of the individuals discontinued the drug because of HPA-axis suppression. The manufacturer states that although systemic effects have been minimal with recommended doses of fluticasone propionate nasal spray, the potential risk of such effects increases with larger doses; therefore, larger-than-recommended doses of fluticasone propionate nasal spray should be avoided. The effect of intranasal fluticasone propionate on the HPA-axis response to stress (e.g., surgery) is not known. Intranasal administration of usual dosages of fluticasone propionate apparently produces less HPA-axis suppression than intranasal administration of usual dosages of dexamethasone phosphate; however, comparative studies have not been conducted to date.

Other Adverse Effects

Headache has been reported in 6.6-16.1% of patients receiving intranasal fluticasone propionate therapy (100-200 mcg once daily). Menstrual cramps also have been reported in patients receiving the drug, although a causal relationship has not been established. Nausea and vomiting have been reported in 2.6-4.8% of adults and children receiving fluticasone (100-200 mcg once daily) in controlled clinical trials. Dizziness, abdominal pain, diarrhea, fever, flu-like symptoms, or aches and pains have been reported in 1-3% of adults and children receiving fluticasone in controlled clinical trials. Drowsiness/lethargy/fatigue or arthralgia has occurred infrequently in patients receiving intranasal fluticasone propionate. Immediate hypersensitivity reactions (e.g., wheezing, contact dermatitis, rash, dyspnea, anaphylaxis/anaphylactoid reactions, pruritus, urticaria, angioedema, edema of the face and tongue, bronchospasm) have been reported during postmarketing surveillance or in controlled clinical trials with intranasal administration of fluticasone propionate.

Cataracts, ocular dryness and irritation, conjunctivitis, blurred vision, glaucoma, and increased intraocular pressure have been reported with intranasal administration of corticosteroids, including fluticasone. In a controlled, comparative study, ophthalmologic abnormalities (e.g., retinal changes, lenticular opacities) were noted after 12 and 24 weeks of therapy in a similar percentage of patients receiving intranasal fluticasone propionate, beclomethasone, or placebo; however, none of the ocular changes were of the type attributed to systemic effects of corticosteroid therapy (e.g., posterior subcapsular cataracts, increased intraocular pressure).

Precautions and Contraindications

Although systemic effects have been minimal with recommended dosages of fluticasone propionate nasal spray, potential risk increases with higher dosages. Therefore, higher than recommended dosages of fluticasone propionate nasal spray should be avoided since hypercorticism and suppression of HPA function may occur. If such systemic effects occur, the dosage of fluticasone propionate nasal spray should be reduced slowly and the drug discontinued in accordance with accepted procedures for discontinuing oral corticosteroid therapy.

Fluticasone propionate nasal spray should be used with caution in patients receiving systemic corticosteroids in an alternate-day or daily dosing regimen for any disease, since concomitant use of the drugs could increase the likelihood of HPA-axis suppression compared with therapeutic dosages of either drug alone. In addition, concomitant use of fluticasone propionate nasal spray with other inhaled corticosteroids could increase the risk of manifestations of hypercorticism and/or suppression of HPA function.

Patients who have received systemic corticosteroids for prolonged periods and are being switched to treatment with topical corticosteroids (e.g., fluticasone propionate nasal spray) should be monitored carefully since corticosteroid withdrawal symptoms (e.g., joint pain, muscular pain, lassitude, depression), acute adrenal insufficiency, or severe symptomatic exacerbation of asthma or other clinical conditions may occur.

Although manifestations of Cushing's syndrome (e.g., hypertension, glucose intolerance, cushingoid features) have not been associated with intranasal fluticasone propionate therapy to date, the possibility of their occurrence should be considered in patients who are particularly sensitive to corticosteroid effects or when usual dosages of the drug are exceeded.

Patients should be advised that intranasal fluticasone propionate should be used at regular intervals to be therapeutically effective. In addition, patients generally should be advised that the full benefits of the drug may not be achieved for several days and that use of topical nasal decongestants or oral antihistamines may be necessary until the effects of intranasal fluticasone propionate therapy are fully manifested. Patients also should be advised not to exceed the prescribed dosage.(See Dosage and Administration: Dosage.) Patients with severe allergies should be instructed to avoid exposure to allergens during intranasal fluticasone propionate therapy to prevent the occurrence of severe allergic symptoms in the eyes and/or lower respiratory tract. Patients should be instructed to contact their physician during intranasal fluticasone propionate therapy if signs or symptoms of the condition do not improve, if the condition worsens, or if sneezing or nasal irritation occurs.

Glucocorticoids, especially in large doses, increase susceptibility to and mask symptoms of infection. Because of the inhibitory effect of these drugs on wound healing, patients with recent nasal septal ulcers, nasal surgery, or nasal trauma should not use intranasal corticosteroids until healing has occurred. Intranasal fluticasone propionate therapy should be used with extreme caution, if at all, in patients with clinical tuberculosis or asymptomatic Mycobacterium tuberculosis infections of the respiratory tract; untreated fungal or bacterial infections; or ocular herpes simplex or untreated, systemic viral infections. During long-term therapy with fluticasone propionate (several months or longer), the nasal passages should be examined periodically for mucosal changes and for signs of candidiasis. If such infections occur, appropriate local treatment of the infection may be necessary and/or discontinuance of intranasal fluticasone propionate therapy may be required.

Patients who are taking immunosuppressant drugs while receiving corticosteroids have increased susceptibility to infections compared with healthy individuals, and certain infections (e.g., varicella [chickenpox], measles) can have a more serious or even fatal outcome in such patients, particularly in children. In patients who have not had these diseases, particular care should be taken to avoid exposure. The relationship of dose, route of administration, and duration of corticosteroid therapy to the risk of developing a disseminated infection is not known, nor is the contribution of the underlying disease and/or prior corticosteroid therapy. Patients receiving corticosteroids who are potentially immunosuppressed should be warned of the risk of exposure to certain infections (e.g., chickenpox, measles) and of the importance of obtaining medical advice if such exposure occurs. If exposure to varicella or measles occurs in such individuals, administration of varicella zoster immune globulin (VZIG) or immune globulin, respectively, may be indicated. If varicella develops, treatment with an antiviral agent (e.g., acyclovir) may be considered. For additional information, and also .

Fluticasone propionate nasal spray is contraindicated in patients with known hypersensitivity to the drug or other ingredients in the formulation (the formulation does not contain fluorocarbons).

Pediatric Precautions

The manufacturer states that safety and efficacy of fluticasone propionate nasal spray in children younger than 4 years of age have not been established.

Use of excessive dosages of corticosteroids may lead to manifestations of hypercorticism, suppression of HPA function, and/or suppression of growth in children or adolescents. Inhibitory effects on short-term growth rate (as determined by knemometry studies of lower leg growth) have been observed in asthmatic children and adolescents receiving orally inhaled corticosteroids (e.g., beclomethasone dipropionate, fluticasone propionate). However, the relationship between short-term changes in lower leg growth and long-term effects on growth currently are unclear. In a placebo-controlled, 1-year study in children 3-9 years of age, normal growth velocity was not adversely affected by intranasal fluticasone propionate 200 mcg once daily. No evidence of clinically relevant changes in HPA axis function (as assessed by 12-hour urinary cortisol excretion) or bone mineral density (as assessed by dual x-ray absorptiometry) was observed in such children. However, therapy with intranasal corticosteroids has caused a reduction in growth velocity in pediatric patients in other controlled clinical trials, even in the absence of laboratory evidence of suppression of HPA function. The potential for fluticasone propionate nasal spray to cause growth suppression in susceptible patients or at dosages exceeding 200 mcg daily cannot be ruled out. The long-term effects of reduction in growth velocity with intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for catch-up growth following discontinuance of treatment with intranasal corticosteroids has not been adequately studied. Clinicians should monitor closely (e.g., via stadiometry) the growth of children and adolescents taking corticosteroids by any route of administration; if growth rate is affected, the clinician should weigh the potential benefits of corticosteroid therapy against the possibility of growth suppression.

Geriatric Precautions

Fluticasone propionate nasal spray has not been evaluated extensively in geriatric patients to date. However, data from US and non-US clinical trials in geriatric patients receiving intranasal fluticasone propionate have not revealed evidence of unusual age-related differences in adverse effects.

Mutagenicity and Carcinogenicity

No evidence of mutagenicity was observed in vitro in prokaryotic or eukaryotic cells when fluticasone propionate was tested in in vitro studies including the Ames microbial (Salmonella typhimurium) mutagen test, Escherichia coli fluctuation test, and Saccharomyces cerevisiae gene conversion test. When tested in in vitro mammalian cell cytogenetic studies, including Chinese hamster ovary and cultured human peripheral lymphocytes, fluticasone propionate did not appear to cause chromosomal damage. No evidence of adverse chromosomal effects was observed in an in vivo micronucleus test in mice receiving high doses of fluticasone propionate by the oral or subcutaneous routes. Furthermore, the drug did not delay erythroblast division in bone marrow.

No evidence of carcinogenicity was seen in mice receiving oral fluticasone propionate dosages up to 1 mg/kg (approximately 20 times the maximum recommended daily intranasal dosage in adults and approximately 10 times the maximum recommended daily intranasal dosage in children on a mcg/m basis) for 78 weeks or in rats receiving inhaled fluticasone propionate dosages up to 57 mcg/kg (approximately 2 times the maximum recommended daily intranasal dosage in adults and approximately equivalent to the maximum recommended daily intranasal dosage in children on a mcg/m basis) for 104 weeks.

Pregnancy, Fertility, and Lactation

Pregnancy

Fluticasone propionate nasal spray should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. Since adrenal insufficiency may occur in neonates born to women who received corticosteroids during pregnancy, these neonates should be monitored carefully for manifestations of this condition. Although there are no adequate and well-controlled studies to date using fluticasone propionate in pregnant women, fluticasone propionate has been shown to be teratogenic and embryotoxic in mice or rats when administered subcutaneously at daily dosages of 45 or 100 mcg/kg, respectively (approximately equivalent to 4 times the maximum recommended daily intranasal dosage in adults based on surface area). Observed fetal toxicity was characteristic of potent glucocorticoid compounds and included embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. Fetal weight reduction and cleft palate were observed in offspring of rabbits given fluticasone propionate 4 mcg/kg subcutaneously (less than the maximum recommended daily intranasal dosage in adults). Following oral administration of up to 300 mcg/kg (approximately 25 times the maximum recommended daily intranasal dosage in adults on a mcg/m basis) daily of fluticasone propionate in rabbits, the drug was not detected in plasma, and no maternal effects nor increased incidence of external, visceral, or skeletal fetal defects was detected. The low bioavailability and small distribution of fluticasone propionate across the placenta may account for the lack of teratogenicity; in rats and rabbits receiving oral fluticasone propionate dosages of 100 mcg/kg (590 mcg/m) or 300 mcg/kg (3.6 mg/m), respectively, less than 0.008% of the dose crossed the placenta. Long-term experience with the use of oral glucocorticoids suggests that rodents are more prone to teratogenic effects of glucocorticoids than humans. In addition, because there is a natural increase in glucocorticoid production during pregnancy, most women will require a lower exogenous glucocorticoid dose and many will not need glucocorticoid treatment during pregnancy.

Fertility

Reproduction studies in rats using subcutaneous fluticasone propionate at daily dosages of 50 mcg/kg (approximately 2 times the maximum recommended daily intranasal dosage in adults on a mcg/m basis) have shown no evidence of impaired fertility. However, prostate weight was substantially reduced in rats at a subcutaneous dose of 50 mcg/kg.

Lactation

Fluticasone propionate should be used with caution in nursing women, since it is not known whether the drug is distributed into milk in humans. Subcutaneous administration of tritiated fluticasone propionate to lactating rats (10 mcg/kg, less than the maximum recommended daily intranasal dosage in adults on a mcg/m basis) resulted in measurable radioactivity in both plasma and milk. Other corticosteroids are distributed into milk and in systemic amounts may cause adverse effects, such as growth suppression, in nursing infants.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Since fluticasone propionate is metabolized in the liver by the cytochrome P-450 (CYP) 3A4 isoenzyme, concomitant use of drugs that affect CYP hepatic microsomal enzymes could alter the metabolism of fluticasone. In a multiple-dose, crossover study, concomitant use of intranasal fluticasone propionate (200 mcg once daily) and ritonavir (100 mg twice daily), a highly potent CYP3A4 inhibitor, increased peak plasma concentrations and area under the plasma concentration-time curve (AUC) of fluticasone, resulting in an 86% decrease in the plasma cortisol AUC. Cushing syndrome and adrenal suppression have been reported during postmarketing experience in patients receiving concomitant therapy with fluticasone propionate and ritonavir. Concomitant use of fluticasone propionate and ritonavir is not recommended unless the potential benefit is considered to outweigh the risk of systemic corticosteroid adverse effects.

Concomitant use of ketoconazole reportedly may inhibit the metabolism of fluticasone through the inhibition of the CYP3A4 system. Administration of a single dose of orally inhaled fluticasone propionate (1 mg or 5 times the maximum daily intranasal dose) in healthy individuals receiving ketoconazole (200 mg once daily until steady-state reached) increased mean plasma fluticasone concentrations, resulting in a depression of certain indices of HPA-axis function (as determined by a reduction in plasma cortisol area under the plasma concentration-time curve). Concomitant administration of multiple doses of erythromycin (333 mg 3 times daily) with orally inhaled fluticasone propionate (500 mcg twice daily) did not affect the pharmacokinetics of fluticasone. Care should be exercised when fluticasone is administered concomitantly with other potent CYP3A4 inhibitors.

Corticosteroids

Concomitant use of fluticasone propionate nasal spray with other inhaled and/or systemically absorbed corticosteroids could increase the risk of hypercorticism and/or suppression of the HPA axis.(See Cautions: Precautions and Contraindications.)

Pharmacokinetics

Limited data are available on the pharmacokinetics of fluticasone propionate following intranasal administration. Because of the drug's low systemic bioavailability when administered intranasally, most pharmacokinetic data for fluticasone propionate are based on studies in which the drug was administered IV or orally.

Absorption

Fluticasone propionate is poorly absorbed from the respiratory and GI tracts following nasal inhalation of the drug as an aqueous spray. Based on indirect calculations, intranasal fluticasone propionate has an absolute systemic bioavailability of less than 2%. A major portion of an intranasal dose of corticosteroids is swallowed and undergoes extensive first-pass metabolism in the liver.(See Pharmacokinetics: Elimination.)In patients with allergic rhinitis receiving intranasal fluticasone propionate for 2-3 weeks, plasma concentrations were above the level of detection of the assay (50 pg/mL) only when recommended dosages were exceeded, and in those instances, only in occasional samples at low concentrations. Current evidence suggests that the therapeutic effects of intranasal fluticasone propionate can be attributed to the topical effects of the drug on the nasal mucosa.

Limited data from studies in which radiolabeled fluticasone propionate has been administered orally indicate that the drug is poorly absorbed from the GI tract and undergoes rapid first-pass metabolism in the liver. Preliminary data from a dose-ranging study suggests that the amount of unchanged fluticasone propionate in plasma increases with dose following oral administration, but the bioavailability of the radiolabeled drug averaged about 1% or less after oral doses of 1-40 mg. Additional studies are needed to determine the oral bioavailability of fluticasone propionate.

Following oral administration of 1 or 16 mg of radiolabeled propionylfluticasone in a few healthy individuals, peak plasma radioactivity levels (expressed as fluticasone propionate equivalents) averaging approximately 1.3 or 9.1 ng/mL, respectively, were achieved within 0.5-6 hours. Since no unchanged fluticasone propionate was detected in plasma for up to 6 hours after oral administration of unlabeled fluticasone propionate given on a separate occasion, the plasma radioactivity noted after administration of the radiolabeled drug was presumed to be fluticasone propionate metabolites. It has been suggested that the presence of small amounts (50-170 pg/mL) of fluticasone propionate in plasma from 6-24 hours after the dose in these individuals potentially may represent rectal reabsorption of unmetabolized drug.

In patients with seasonal or perennial allergic or nonallergic rhinitis, the onset of symptomatic relief may occur within 12-48 hours of initiation of intranasal fluticasone propionate therapy in adults and within 36 hours in children; however, up to 2-4 days generally are required for optimum effectiveness in most patients. Following discontinuance of intranasal fluticasone propionate therapy, symptoms of rhinitis generally do not recur for 1-2 weeks.

Distribution

Although fluticasone propionate is widely distributed into most tissues following IV administration, distribution of the drug following intranasal administration has not been described. Following IV administration, the volume of distribution for fluticasone propionate is 4.2 L/kg. Fluticasone propionate is approximately 91% bound to human plasma proteins; protein binding demonstrates no obvious relationship to drug concentration. Fluticasone propionate is weakly and reversibly bound to erythrocytes and equilibrates freely between erythrocytes and plasma. Fluticasone propionate is not appreciably bound to human transcortin (corticosteroid-binding globulin).

Fluticasone propionate crosses the placenta in rats or rabbits following oral administration of fluticasone propionate 100 or 300 mcg/kg, respectively (approximately 4 or 25 times, respectively, the maximum daily intranasal dosage in adults on a mcg/m basis). It is not known if fluticasone propionate is distributed into human milk following intranasal administration; however, other corticosteroids are distributed into human milk. In lactating rats, subcutaneous administration of tritiated fluticasone propionate (10 mcg/kg, approximately one-third the maximum recommended daily intranasal dosage in adults on a mcg/m basis) resulted in measurable radioactivity in both plasma and milk.

Elimination

The apparent elimination half-life of fluticasone propionate after IV administration is approximately 3 hours. Plasma clearance of the drug ranges from 623-998 mL/minute; total blood clearance (plasma clearance adjusted for packed cell volume) of IV fluticasone propionate averages 1093 mL/minute and approximates that of liver blood flow, with renal clearance accounting for less than 0.02% of total body clearance.

Fluticasone propionate is rapidly metabolized in the liver by the cytochrome P-450 isoenzyme CYP3A4; the principal metabolite is the inactive 17β-carboxylic acid derivative. Following oral administration of radiolabeled drug, less than 5% of the dose was excreted in urine. Of the total radioactivity recovered in urine, 18% represented the inactive 17β-carboxylic acid derivative of fluticasone propionate, 12% represented a less polar metabolite, and the remainder represented more polar metabolites. Total fecal excretion of fluticasone propionate has been reported to range from 87-100% of the oral dose. In 2 healthy men receiving oral fluticasone propionate, fecal recovery of unchanged drug was 9 and 20% after a 1-mg dose and 54 and 75% after a 16-mg dose. The increase in fecal excretion of unchanged fluticasone propionate with increased dose has been attributed to insolubility of the drug rather than to biliary elimination. The 17β-carboxylic acid metabolite of fluticasone propionate accounted for 3-40% of fecal excretion. When a single oral 5-mg dose of fluticasone propionate was administered to patients with an ileostomy, 73% of the dose was recovered in the ileostomy effluent within 12 hours.

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