Flunisolide dosing

Inhaled steroids (commonly used are beclomethasone, budesonide, triamcinolone, fluticasone, flunisolide) appear to attenuate the inflammatory response, to reduce bronchial hyperreactivity, to decrease exacerbations and to improve health status they may also reduce the risk of myocar dial infar ction, but they do not modify the longterm decline in lung function. Whether- steroids affect mortality remains unclear. Many patients appear to be resistant to steroids and large, long-term trials have shown only limited effectiveness of inhaled corticosteroid ther apy. Certainly, the benefit from steroids is smaller in COPD than in asthma. Topical side-effects of inhaled steroids are oropharyngeal candidiasis and hoarse voice. At the normal doses systemic side-effects of inhaled steroids have not been firmly established. The current recommendation is that the addition of inhaled gluco-coiticosteroids to bronchodilator treatment is appropriate for patients with severe to veiy sever e COPD. 

Intranasal steroids are considered to have a slow onset of action (12-24 hours). Some patients may experience relief within a few days. Maximum treatment response may take up to several weeks to be observed.9,10,12 To achieve optimal effects, use at regular intervals is recommended.15 With the exception of beclomethasone and flunisolide, which are administered twice daily, the recommended doses for the intranasal corticosteroids are one to two sprays in each nostril once daily.15... 

Beclomethasone dipropionate, triamcinolone acetonide, budesonide, flunisolide, and mometasone furoate are available as nasal sprays for the topical treatment of allergic rhinitis. They are effective at doses (one or two sprays one, two, or three times daily) that in most patients result in plasma levels that are too low to influence adrenal function or have any other systemic effects. 

Nasarel is a metered-dose manual-pump spray unit containing 0.025% w/w flunisolide in an aqueous medium containing benzalkonium chloride, butylated hydroxytol-uene, citric acid, edetate disodium, polyethylene glycol 400, polysorbate 20, propylene glycol, sodium citrate... 

G. Dickens, D. Wermeling, C. Matheney, W. John, W. Abramowitz, S. Sista, T. Foster, and C. S., Flunisolide administered via metered dose inhaler with and without spacer and following oral administration, J. Allergy Clin. Immunol. 103, S135 (1999) 703 S132 (1999). 

S. P. Newman, J. Brown, K. P. Steed, S. J. Reader, and H. Kladders, Lung deposition of fenoterol and flunisolide delivered using a novel device for inhaled medicines Comparison of RESPIMAT with conventional metered-dose inhalers with and without spacer devices, Chest 113 951 (1998). 

Nasal sprays are available as squeeze bottles, which would not be expected to give reproducible dosing. They are also available as metered-dose devices, which would be expected to give more reproducible dosing, as a mechanical actuation delivers a pre-determined volume to the patient. Thus the dose of drag received by the patient will be dependent on the concentration of drag in the formulation. Commercial examples of metered-dose sprays include Syntaris, Beconase and Rhinocort which deliver flunisolide, beclomethasone and budesonide respectively. 

As a nasal spray, flunisolide is effective in allergic rhinitis in clinical use [32-34], and their protective effects in patients with bronchial asthma have also been studied. The efficacy and safety of a new metered-dose inhaler of flunisolide has recently been reported [35]. 

The equivalence of inhaled glucocorticoids based on equipotent (cortisol suppression) effects has been studied by the Asthma Clinical Research Network (ACRN). Six different inhaled glucocorticoids and matched placebos (beclomethasone chlorofluorocarbon, budesonide dry powder inhaler, fluticasone dry powder inhaler, fluticasone chlorofluorocarbon metered-dose inhaler, flunisolide chlorofluorocarbon, and triamcinolone chlorofluorocarbon) were compared by measuring their systemic effects (18). 

In another study, different doses of flunisolide hydrofluoroalkane were tested in 21 healthy adult volunteers for 4.5 days (170, 340, and 680 pg) there was a dose-related response after both single- and multiple-dose administration (22). There was no accumulation of flunisolide with repeated dosing, suggesting that the systemic availability of flunisolide hydrofluoroalkane is low. A randomized, double-blind, placebo-controlled study with daily doses of 80 and 160 pg over 12 weeks in 353 asthmatic children gave similar results (23). 

Nolting A, Abramowitz W. Multiple-dose proportionahty study of flunisolide hydrofluoroalkane. Allergy Asthma Proc 2002 23(5) 311-18. 

In asthmatic human patients, fluticasone propionate improves asthma symptoms and parameters, improves pulmonary function and reduces pulmonary inflammation and airway reactivity (Barnes et al 1998). Regular fluticasone reduces or eliminates the need for rescue 2 agonist therapy and produces progressive improvement in airway reactivity and pulmonary function. In clinical studies, equivalent efficacy is demonstrated with one-quarter of the dose of fluticasone compared with flunisolide and budesonide, and equivalent efficacy is demonstrated with one-half of the dose of fluticasone compared with beclometasone. Adrenal function is less affected by fluticasone propionate at therapeutic doses than with beclometasone, flunisolide or budesonide. Although all aerosolized corticosteroids are considered safe, fluticasone has the least potential for adverse systemic effects and has the most favorable therapeutic index. 

Flunisolide. The portion of a Bunisolide (AetoBid, Nasarel) dose that is. swallowed is rapidly converted to the 6/3-hydroxy metabolite after first-pass metabolism in the liver. Tlie 6/ hydroxy metabolite is approximately as active as hydrocortisone itself, but the small amount produced usually has limited systemic effects. Water-soluble conjugates are inactive. 

The metered-dose aerosol inhaler is not only a most convenient system for the delivery of therapeutically active drugs but it has proven to be a life-saving device for many asthmatics. This system has made it possible for millions of asthma sufferers to lead normal lives. The convenience of self-administering a dose of drug accurately and quickly has made the metered-dose aerosol the dosage form of choice for the delivery of drugs to the respiratory system. From epinephrine to albuterol, from triamcinolone to flunisolide, from proteins and peptides to hormones, this dosage form has proven its value. 

In scintigraphic studies using fenoterol and flunisolide, mean drug delivery to the lungs was 31-45% of the dose delivered using Respimat compared with less than 20% using a CFC MDI. Safety profiles did not differ between Respimat and CFC MDI administration. Facial deposition data suggested a low risk of untoward effects even in potential misuse situations for Respimat. 

The ICSs beclomethasone dipropionate, budesonide, flunisolide, fluticasone propionate, and triamcinolone acetonide that are currently available for use are compared and listed in Table 26-12. The ICSs have pharmacokinetic differences that result in different topical/ systemic activity. Most evidence is consistent with log-linear dose-response curves for both indirect and direct responses. The log-linear nature of the dose-response curve for corticosteroid activity raises the issue of how much of a difference in dose (or lung delivery) or potency is detectable. The dose-response curves for the ICSs are relatively flat primarily because all the measures used to assess efficacy (lung function, BHR, symptoms, and as-needed short-acting inhaled /32-agonist use) are downstream events from the anti-inflammatory activity. In general, it takes a fourfold difference in potency or dose to detect clinically significant differences. The table of comparative doses (see Table 26-12) is based on extensive comparative clinical trials. Clinical comparative doses take into consideration potency differences as well as lung delivery differences from the various devices. 

Flunisolide is an extremely potent synthetic fluorinated glucocorticoid. It is administered by metered dose inhaler. 

Flunisolide nasal solution is available in an aqueous solubilized form, which delivers 25 pg per spray. The total daily adult dose for flunisolide from the nasal spray is 200 to 400 pg. Flunisolide inhalation aerosol for pulmonary delivery is a microcrystalline suspension in a chlorofluorocarbon propellant that delivers 250 pg per metered spray. The total daily adult inhalation dose for flunisolide is 1,000 pg. Doses exceeding 2,000 pg/day need to be monitored for FIFA suppression. 

Dickens GR, Wermeling DP, Matheny CJ, et al. Pharmacokinetics of flunisolide administered via metered dose inhaler with and without a spaoer devioe and following oral administration. Ann Allergy Asthma Immunol 2000 84 528-532. 

Flunisolide is an acetone ketal (acetonide) with a 6a-fluoro group and a free C-21 hydroxyl group. The acetonide decreases mineralocorticoid activity, and the 6a-fluoro group increases glucocorticoid activity. It is not a prodrug, because it has the free hydroxyl group at C-21. Flunisolide has approximately 20% of the receptor affinity as budesonide, and approximately 40% of the inhaled dose is systemically bioavailable. Flunisolide is quickly metabolized by CYP3A4 to the 6p-hydroxy metabolite, which has less than 1% of the activity of the parent compound. This,... 

Mann M, Eliasson O, Patel K, ZuWallack RL. A comparison of the effects of bid and qid dosing on comphance with inhaled flunisolide. Chest 1992 101 496-499. 

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