Flovent

[Fluticasone Propionate]

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:

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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).

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/ m 2 ) 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/ m 2 ) 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/ m 2 ) 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/ m 2 , 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/ m 2 ). However, following oral administration of up to 300 mcg/ kg (approximately 3 times the maximum human daily inhalation dose based on mcg/ m 2 ) 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/ m 2 , 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/ m 2 ) 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.

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