During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement of respiratory function.
Fluticasone propionate will often permit control of asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since fluticasone propionate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of FLOVENT (fluticasone propionate) Inhalation Aerosol in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. A relationship between plasma levels of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown after 4 weeks of treatment with FLOVENT (fluticasone propionate) Inhalation Aerosol. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing FLOVENT (fluticasone propionate) Inhalation Aerosol.
Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with these drugs should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.
It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients, particularly when FLOVENT (fluticasone propionate) Inhalation Aerosol is administered at higher than recommended doses over prolonged periods of time. If such effects occur, fluticasone propionate inhalation aerosol should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms.
A reduction of growth velocity in children or teenagers may occur as a result of inadequate control of chronic diseases such as asthma or from use of corticosteroids for treatment. Physicians should closely follow the growth of adolescents taking corticosteroids by any route and weigh the benefits of corticosteroid therapy and asthma control against the possibility of growth suppression if an adolescent s growth appears slowed.
The long-term effects of fluticasone propionate in human subjects are not fully known. In particular, the effects resulting from chronic use of fluticasone propionate on developmental or immunologic processes in the mouth, pharynx, trachea, and lung are unknown. Some patients have received fluticasone propionate inhalation aerosol on a continuous basis for periods of 3 years or longer. In clinical studies with patients treated for nearly 2 years with inhaled fluticasone propionate, no apparent differences in the type or severity of adverse reactions were observed after long- versus short-term treatment.
Rare instances of glaucoma, increased intraocular pressure, and cataracts have been reported following the inhaled administration of corticosteroids, including fluticasone propionate.
In clinical studies with inhaled fluticasone propionate, the development of localized infections of the pharynx with Candida albicans has occurred. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy while remaining on treatment with FLOVENT (fluticasone propionate) Inhalation Aerosol, but at times therapy with FLOVENT (fluticasone propionate) Inhalation Aerosol may need to be interrupted.
Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial, viral or parasitic infections; or ocular herpes simplex.
In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions, with some patients presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate. Cases of serious eosinophilic conditions have also been reported with other inhaled corticosteroids in this clinical setting. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between fluticasone propionate and these underlying conditions has not been established (see ADVERSE REACTIONS).
Information for Patients
Patients being treated with FLOVENT (fluticasone propionate) Inhalation Aerosol 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 use FLOVENT (fluticasone propionate) Inhalation Aerosol at regular intervals as directed. Results of clinical trials indicated significant improvement may occur within the first day or two of treatment; however, the full benefit may not be achieved until treatment has been administered for 1 to 2 weeks or longer. The patient should not increase the prescribed dosage but should contact the physician if symptoms do not improve or if the condition worsens.
After inhalation, rinse the mouth with water without swallowing.
Patients should be warned to avoid exposure to chickenpox or measles and, if they are exposed, to consult the physician without delay.
For the proper use of FLOVENT (fluticasone propionate) Inhalation Aerosol and to attain maximum improvement, the patient should read and follow carefully the Patient s Instructions for Use accompanying the product.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Fluticasone propionate demonstrated no tumorigenic potential in studies of oral doses up to 1,000 mcg/kg (approximately 2 times the maximum human daily inhalation dose based on mcg/m2) for 78 weeks in the mouse or inhalation of up to 57 mcg/kg (approximately 1/4 the maximum human daily inhalation dose based on mcg/m2) for 104 weeks in the rat.
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 when administered at high doses by the oral or subcutaneous routes. Furthermore, the compound did not delay erythroblast division in bone marrow.
No evidence of impairment of fertility was observed in reproductive studies conducted in rats dosed subcutaneously with doses up to 50 mcg/kg (approximately 1/4 the maximum human daily inhalation dose based on mcg/m2) in males and females. However, prostate weight was significantly reduced in rats.
Teratogenic Effects: Pregnancy Category C. Subcutaneous studies in the mouse and rat at 45 and 100 mcg/kg, respectively (approximately 1/10 and 1/2 the maximum human daily inhalation dose based on mcg/m2, respectively), revealed fetal toxicity characteristic of potent glucocorticoid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification.
In the rabbit, fetal weight reduction and cleft palate were observed following subcutaneous doses of 4 mcg/kg (approximately 1/25 the maximum human daily inhalation dose based on mcg/m2). However, following oral administration of up to 300 mcg/kg (approximately 3 times the maximum human daily inhalation dose based on mcg/m2) of fluticasone propionate to the rabbit, there were no maternal effects nor increased incidence of external, visceral, or skeletal fetal defects. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration (see CLINICAL PHARMACOLOGY).
Less than 0.008% of the administered dose crossed the placenta following oral administration of 100 mcg/kg to rats or 300 mcg/kg to rabbits (approximately 1/2 and 3 times the maximum human daily inhalation dose based on mcg/m2, respectively).
There are no adequate and well-controlled studies in pregnant women. FLOVENT (fluticasone propionate) Inhalation Aerosol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Experience with oral glucocorticoids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from 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.
It is not known whether fluticasone propionate is excreted in human breast milk. Subcutaneous administration of 10 mcg/kg tritiated drug to lactating rats (approximately 1/20 the maximum human daily inhalation dose based on mcg/m2) resulted in measurable radioactivity in both plasma and milk. Because glucocorticoids are excreted in human milk, caution should be exercised when fluticasone propionate inhalation aerosol is administered to a nursing woman.
One hundred thirty-seven (137) patients between the ages of 12 and 16 years were treated with FLOVENT (fluticasone propionate) Inhalation Aerosol in the US pivotal clinical trials. The safety and effectiveness of FLOVENT (fluticasone propionate) Inhalation Aerosol in children below 12 years of age have not been established. Oral corticosteroids have been shown to cause a reduction in growth velocity in children and teenagers with extended use. If a child or teenager on any corticosteroid appears to have growth suppression, the possibility that they are particularly sensitive to this effect of corticosteroids should be considered (see PRECAUTIONS).
Five hundred seventy-four (574) patients 65 years of age or older have been treated with FLOVENT (fluticasone propionate) Inhalation Aerosol in US and non-US clinical trials. There were no differences in adverse reactions compared to those reported by younger patients.