Particular care is needed for patients who are transferred from systemically active corticosteroids to FLOVENT Inhalation Aerosol because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of HPA function.
Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although FLOVENT Inhalation Aerosol may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.
During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.
A drug interaction study 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 and PRECAUTIONS: 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.
Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to FLOVENT Inhalation Aerosol. In a trial of 96 patients, prednisone reduction was successfully accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during transfer to inhaled fluticasone propionate. Successive reduction of prednisone dose was allowed only when lung function, symptoms, and as-needed beta-agonist use were better than or comparable to that seen before initiation of prednisone dose reduction. Lung function (FEV1 or AM PEF), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.
Transfer of patients from systemic corticosteroid therapy to FLOVENT Inhalation Aerosol may unmask conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, eczema, and arthritis.
Persons who are on 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 on corticosteroids. In such children or adults who have not had these diseases, 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 exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If 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 develops, treatment with antiviral agents may be considered.
FLOVENT Inhalation Aerosol is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm.
As with other inhaled asthma medications, bronchospasm may occur with an immediate increase in wheezing after dosing. If bronchospasm occurs following dosing with FLOVENT Inhalation Aerosol, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with FLOVENT Inhalation Aerosol should be discontinued and alternative therapy instituted.
Patients should be instructed to contact their physicians immediately when episodes of asthma that are not responsive to bronchodilators occur during the course of treatment with FLOVENT Inhalation Aerosol. During such episodes, patients may require therapy with oral corticosteroids.
General: 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 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 Inhalation Aerosol. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing FLOVENT 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 cortico-steroid 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 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 Inhalation Aerosol, but at times therapy with FLOVENT 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.
Eosinophilic Conditions: 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 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 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 Inhalation Aerosol and to attain maximum improvement, the patient should read and follow carefully the Patient's Instructions for Use accompanying the product.
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) with multiple doses of ketoconazole (200 mg) to steady state resulted in increased mean plasma fluticasone propionate exposure, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol. Caution should be exercised when FLOVENT Inhalation Aerosol is coadministered with ketoconazole and other known potent cytochrome P450 3A4 inhibitors.
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.
Pregnancy: 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 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.
Nursing Mothers: 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.
Pediatric Use: One hundred thirty-seven (137) patients between the ages of 12 and 16 years were treated with FLOVENT Inhalation Aerosol in the US pivotal clinical trials. The safety and effectiveness of FLOVENT 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).
Geriatric Use: Five hundred seventy-four (574) patients 65 years of age or older have been treated with FLOVENT Inhalation Aerosol in US and non-US clinical trials. There were no differences in adverse reactions compared to those reported by younger patients.