Flunisolide: A Review of its Pharmacological Properties and Therapeutic Efficacy in Rhinitis

Summary

Synopsis: Flunisolide¹, a derivative of fluocinolone acetonide, is advocated for intranasal inhalation for the treatment of perennial and seasonal allergic rhinitis. It is rapidly absorbed by all routes of administration, but it quickly undergoes extensive first-pass metabolism to a 6β-hydroxylated metabolite, which possesses only weak corticosteroid effects. Intranasal flunisolide relieves nasal symptoms (but not eye symptoms) in both perennial and seasonal allergic rhinitis, being most effective in patients who have an allergic component to their rhinitis; and like other intranasal corticosteroids it may reduce the need for systemic antihistamines in such patients, especially during peak pollen periods. A few well designed comparative studies have shown flunisolide to be as effective as intranasal beclomethasone, and (in a single study) more effective than intranasal sodium cromoglycate solution.

Only transient side effects have occurred, including nasal stinging and throat irritation. No Candida infections have been clinically apparent in short or longer term trials. Resting morning plasma cortisol levels have not been suppressed by usual therapeutic doses of intranasal flunisolide, but the drug’s effects on hypothalamo-pituitary-adrenal (HPA) axis integrity during conditions of stress have not been evaluated.

Pharmacology: In animal studies flunisolide has several hundred times the anti-inflammatory, thymolytic and anti-adrenocorticotrophic hormone activities of hydrocortisone. It has been shown in animal models to reduce inflammation after topical application, and in man to cause cutaneous vasoconstriction with an activity similar to beclomethasone dipropio-nate and triamcinolone acetonide. Inhaled flunisolide has an eosinophil suppressive potency one-third that seen with the intravenous route. Unlike systemically administered corticosteroids, inhaled flunisolide does not impair neutrophil chemotaxis.

Administration of intranasal flunisolide for several months did not produce drug related abnormalities on nasal biopsy. A small nasal septal perforation waxted in a single patient receiving flunisolide, but whether this was related to flunisolide treatment was unclear.

Pharmacokinetic Studies: Flunisolide is rapidly absorbed following oral ingestion and bronchial or intranasal inhalation. Systemic bioavailability is 21 %, 39 % and 49 % when it is administered orally, by inhalation and intranasally, respectively. After intranasal inhalation, peak plasma concentrations are reached in 10 to 30 minutes. Flunisolide has a relatively large volume of distribution (about 1.8L/kg) in man and is widely distributed to body tissues in rats. In man, it undergoes rapid and extensive first-pass metabolism to a 6β-hydroxylated metabolite, which has less than 0.01 times the potency of flunisolide, and is less than 3 times as potent as hydrocortisone. The plasma elimination half-life of flunisolide is about 1.8 hours by all routes of administration. After intravenous or oral administration flunisolide is excreted in the urine (about 50% ) and faeces (about 40%), mainly as the 6β-hydroxylated metabolite and conjugates.

Therapeutic Trials: Flunisolide has been studied in a number of placebo controlled trials and in a few well designed comparative studies with other agents. Intranasal flunisolide (150 to 300µg daily) was usually clearly more effective than a placebo in relieving most nasal symptoms of rhinitis (e.g. sneezing, stuffy or runny nose, nose blowing, postnasal drip), but not eye symptoms, and was judged superior to a placebo by about 70% of patients in most studies. It was particularly effective in rhinitis with a clearly demonstrable allergic component (e.g. high immunoglobulin E levels, eosinophilia, positive skin tests); indeed, it was ineffective in a single study conducted entirely in patients with nonallergic perennial rhinitis. As with other intranasal corticosteroids, the need for systemic antihistamines is often reduced in patients with allergic rhinitis receiving flunisolide. In a few well designed comparative studies, flunisolide was as effective as usual doses of intranasal beclomethasone dipropionate in seasonal allergic or perennial (usually allergic) rhinitis, and was more effective than in-tranasal sodium cromoglycate solution in a single study in seasonal allergic rhinitis.

Side Effects: Intranasal flunisolide is generally well tolerated, producing only transient nasal stinging and throat irritation. It has not altered haematological or biochemical laboratory parameters. No Candida infections were clinically apparent in rhinitis patients in the short or longer term (up to a year in a small number of patients) trials which have been reported, although Candida colonisation was present in 2 patients. However, such findings are not likely clinically important. Although resting morning plasma cortisol levels have not been suppressed by usual therapeutic doses of intranasal flunisolide, effects on hypothalamo-pituitary-adrenal axis integrity during conditions of stress in patients receiving flunisolide have not been evaluated.

Dosage: Flunisolide is available as a metered pump aerosol delivering 25µg per spray. In the treatment of rhinitis the recommended dosage is 2 sprays per nostril twice daily (200µg daily), increasing to 2 sprays 3 times daily if required. In children 1 spray 3 times daily is recommended.