Intranasal Corticosteroids

Intranasal corticosteroids are highly effective in preventing and relieving nasal symptoms associated with both early- and late-phase allergic responses.[7, 29, 30] In general, they relieve nasal congestion and itching, rhinorrhea, and sneezing, and in some studies they almost completely prevented late-phase symptoms.[9, 31, 32] Although some relief may occur within a few days, a full response to the drugs may take up to several weeks.[32, 33]

The mechanism of action of intranasal corticosteroids is complex and somewhat of a mystery. It is not known if the agents penetrate the nasal mucosa or act on target cells. Corticosteroids have specific effects on mediators and on the inflammatory cells involved in the allergic process. Mediators that appear to be affected include prostaglandins, leukotrienes, and mast cells.[34] The drugs also act by inhibiting T lymphocytes, particularly TH2 cells, and responses such as cytokine production or action and eosinophil recruitment.[8, 16, 34]

The rationale for topical corticosteroids in the treatment of allergic rhinitis is that adequate drug concentrations can be achieved at receptor sites in the nasal mucosa. This leads to symptom control and reduces the risk of systemic adverse effects.[34-36] Whereas all available intranasal corticosteroids are safe and effective for this indication, differences in efficacy, side effects, and clinical attributes must be considered.[37-39]

Topical potency of corticosteroids usually is determined by degree of cutaneous vasoconstrictive activity from a skin model. With this model, two products, fluticasone propionate and mometasone furoate, are more potent than other intranasal corticosteroids.[6, 29] The degree of vasoconstriction does not directly correlate with antiinflammatory potency but does explain part of the clinical efficacy of the drugs in allergic rhinitis.[34] Another measure of potency relates to glucocorticoid receptor-binding affinity. One study determined a rank order of receptor-binding affinity (lowest to highest) to be dexamethasone, triamcinolone acetonide, budesonide, fluticasone propionate, and mometasone furoate.[40] In a similar study, fluticasone had higher affinity than the active metabolite of beclomethasone, dexamethasone, and budesonide.[41]

Lipophilicity is an important consideration based on the fact that highly lipophilic agents have a greater degree and faster rate of absorption into the nasal mucosa than less lipophilic drugs and therefore enhanced ability to reach the glucocorticoid receptor due to longer retention time in nasal tissue.[6, 34] A study determined the rank order of lipid solubility of intranasal corticosteroids, from lowest to highest, to be flunisolide, triamcinolone acetonide, budesonide, beclomethasone dipropionate, fluticasone propionate, and mometasone furoate.[42] Lipophilicity characteristics and systemic bioavailability can be influenced by the performance of the inhaler device. Several studies are evaluating delivery devices and formulations to determine if they differ significantly with respect to clinical outcomes or adverse reactions.[43]

Another concern regarding topical intranasal corticosteroids is their ability to cause systemic adverse reactions. Systemic absorption can be broken down into two aspects: amount of drug absorbed through the nasal mucosa, and fraction of the dose that is swallowed and absorbed through the gastrointestinal tract.[6, 8, 44] Mometasone furoate and fluticasone propionate have very low systemic bioavailability, 0.1% and less than 2%, respectively, and are believed to be poorly absorbed into systemic circulation due

to high lipophilicity.[44-47] Other inhaled corticosteroids have oral bioavailabilities ranging between 20% and 50%, with the exceptions of triamcinolone acetonide and beclomethasone whose bioavailability is not provided in product labeling.[48-51]

Although therapy at normal dosages generally is considered safe, it is impossible to dismiss that prolonged use of topical nasal steroids may result in systemic side effects. Traditionally, hypothalamic-pituitaryadrenal (HPA) axis function has been measured to determine the drugs' systemic activity. These analyses can be divided into tests to evaluate basal versus dynamic function, and have been used as biologic markers for systemic activity.[6, 52] Reviews of clinical studies explored the effects of intranasal steroids on the basal index function (by measuring cortisol levels) and generally showed no significant effects of beclomethasone dipropionate 200-800 g/day, triamcinolone acetonide 220 g/day, fluticasone propionate 200 g/day, and mometasone furoate 200 g/day.[53-56] Conflicting evidence was found for budesonide; in one study dosages of 200, 400, and 800 g/day caused significant suppression of urinary cortisol, whereas in another study budesonide 200 g/day did not.[54, 55] Studies that attempted to determine the effect of intranasal steroids on dynamic function (by evaluating adrenocorticotropic stimulation) similarly showed no significant effects with beclomethasone dipropionate 336 g/day, fluticasone propionate 200 and 400 g twice/day, or triamcinolone acetonide 220 and 400 g/day.[57-59] These data suggest that the drugs have little or no effect on the HPA axis when administered at recommended dosages.

Effects of inhaled steroids in short-term treatment of asthmatic children raised questions and prompted studies to determine their effect on growth. Similar concerns were expressed with long-term therapy of intranasal corticosteroids. A small, but statistically significant reduction in growth velocity was reported in a 12-month study of young children (aged 6-9 yrs) treated for perennial allergic rhinitis with beclomethasone dipropionate 336 g/day.[60] The treated group had slower growth rates of 0.013 cm/day or 5 cm/year compared with a group receiving placebo, 0.017 cm/day or 5.9 cm/year.[60] Data evaluating the effects of nasal inhaled steroids on children are limited. Questions that future investigations could address include which agents significantly affect growth, whether growth returns to normal after the drug is stopped, and whether there is an additive effect when concomitant oral and inhaled steroids are administered for treatment of asthma.[6]

Therapy with intranasal corticosteroids frequently results in some form of nasal irritation. Local side effects of dryness, burning and stinging, and sneezing, together with headache and epistaxis occur in 5-10% of patients regardless of formulation or compound.[6, 29, 46, 48-51, 61, 62] Septal perforations are rare and can be avoided by counseling patients on appropriate administration technique of averting the spray away from the septum and avoiding trauma from the delivery tip.[8] There have been rare reports of patients who developed contact dermatitis on the nose, cheeks, and upper lip from budesonide nasal spray.[62] Mometasone

Mometasone furoate is a synthetic corticosteroid that is available in an aqueous suspension and administered by metered-dose manual pump spray delivering 50 g for the treatment of seasonal and perennial allergic rhinitis. Unlike other intranasal corticosteroids, it is approved for adults and for children aged 3 years and older.[63]

Mometasone is at least as effective as beclomethasone and fluticasone for perennial allergic rhinitis. A comparison of mometasone furoate 100 g once/day, mometasone furoate 200 g once/day,

beclomethasone 200 g twice/day, and placebo found no statistical difference in symptom relief between the two dosages of mometasone.[64] The dosage of 200 g/day was statistically superior to placebo and was as effective as beclomethasone at all time points for relief of total nasal symptoms (congestion, rhinorrhea, sneezing, nasal itching). In a similar study of mometasone furoate 200 g once/day, beclomethasone 200 g twice/day, and placebo, both active treatments significantly reduced patient-rated total nasal symptoms from baseline and maintained that response throughout the 3-month study. Both mometasone and beclomethasone led to significant reductions in symptom severity at all time points as compared with placebo.[65] In a study of mometasone 200 g/day, fluticasone 200 g/day, and placebo for perennial allergic rhinitis, the two active drugs were equivalent to each other and superior to placebo in their ability to decrease severity scores and total nasal symptoms, and to provide a greater number of symptom-free days.[66]

One group compared mometasone furoate 200 g once/day, beclomethasone dipropionate 168 g twice/day, and placebo in patients with moderate-to-severe seasonal allergic rhinitis.[67] Prophylactic treatment with either active drug resulted in a significantly higher proportion of days with minimal to no symptoms during allergy season than placebo. Mean symptom scores before the onset of allergy season were significantly lower in the mometasone group than in either the beclomethasone or placebo group.

In a comparison of mometasone furoate nasal spray with placebo, 28% of patients experienced clinically significant symptom relief within 12 hours after the first dose of mometasone compared with 13% for placebo (p<0.01). The median time to achieve moderate or better relief was approximately 36 hours with mometasone versus over 72 hours for placebo.[68] Fluticasone

The efficacy of intranasal fluticasone has been widely studied. In several trials the drug was highly effective in treating seasonal allergic rhinitis by improving sneezing, nasal itching, nasal blockage, and rhinorrhea. It also increased the number of symptom-free days and reduced the need for rescue drugs, such as antihistamines, compared with placebo.[30]

Fluticasone propionate is available in an aqueous formulation and administered by metered-dose manual pump spray. Each 100 mg of spray contains 50 g of the active agent and is approved for use in adults and children aged 4 years and older.[46]

In comparative studies, fluticasone 200 g/day was equally effective as other intranasal corticosteroids including beclomethasone 336-400 g/day, flunisolide 200 g/day, and triamcinolone acetonide 220 g/day.[30] However, in a 6-week study, although fluticasone 200 g/day was equally effective as budesonide 128 g/day, it did not appear to be as effective as budesonide 256 g/day in decreasing sneezing.[69]

The efficacy of fluticasone 100 g twice/day, fluticasone 200 g once/day, and placebo was assessed in patients with seasonal allergic rhinitis.[70] Both dosages of fluticasone increased the number of symptomfree days and improved nasal symptom severity scores significantly more than placebo.

In several large, double-blind, placebo-controlled studies in patients with perennial allergic rhinitis, fluticasone propionate was associated with significant improvements in nasal symptoms and prolongation of number of symptom-free days.[71, 72] In addition, fluticasone propionate 200 g once/day and beclomethasone dipropionate 168 g twice/day were clinically equivalent in both 3- and 6-month evaluations.[73, 74] Budesonide

Budesonide is indicated for treatment of seasonal and perennial allergic rhinitis in adults and children aged 6 years and older. It is available in an aerosol metered-dose canister that delivers 32 g of micronized budesonide/activation, and an aqueous formulation in a metered-dose nonaerosol pump spray that delivers 64 g/spray.[50, 51]

Relatively few trials have evaluated budesonide, beclomethasone dipropionate, flunisolide, and triamcinolone acetonide. In a comparison of budesonide 400 g once/day, mometasone furoate 200 g once/day, and placebo, both active drugs prevented symptoms of seasonal allergic rhinitis from occurring for a significantly higher proportion of days after the start of allergy season, and both significantly reduced nasal symptoms compared with placebo.[75] The median length of time to the first day with more than minimal symptoms was significantly longer for active treatments: 26 days for mometasone furoate, 34 days for budesonide, and 9 days for placebo. Budesonide was at least equally effective as, if not superior to, beclomethasone in clinical trials for relieving nasal symptoms and overall symptoms of seasonal allergic rhinitis.[76, 77]

In a study examining the efficacy of budesonide 256 g once/day, fluticasone 200 g once/day, and placebo for the treatment of perennial allergic rhinitis, budesonide significantly reduced combined symptoms compared with fluticasone and placebo. It also was superior to fluticasone in relieving nasal blockage (p<0.01).[78] Flunisolide

Flunisolide is an intranasal corticosteroid, approved for treating seasonal and perennial allergic rhinitis in adults and children aged 6 years and older. It is available in an aqueous solution and administered by metered-dose manual pump spray that delivers 25 g/activation.[48, 49] The two formulations of flunisolide, Nasalide and Nasarel, are not bioequivalent. The frequency and nature of adverse events also differ. Nasalide was associated with more reports of nasal burning and stinging, and Nasarel with more problems related to taste.[79]

According to early reports of tolerability, up to 45% of patients noted nasal burning with Nasalide nasal spray.[8, 49] However, some of these problems were due to the formulation. In the 1980s the drug was reformulated to contain less propylene glycol (Nasarel), and this resulted in a significantly lower frequency of nasal burning and stinging as well as throat irritation.[80, 81] When this formulation was compared with beclomethasone, it had a similar frequency of nasal or pharyngeal irritation but greater frequency of mild aftertaste.[82]

Three studies comparing beclomethasone dipropionate and flunisolide in patients with seasonal allergic rhinitis found the two drugs to be equally effective. Intranasal flunisolide and beclomethasone were assessed in a randomized, single-blind, parallel-group study.[83] Patient-reported assessments of sneezing, stuffy nose, runny nose, nose blowing, postnasal drip, epistaxis, and eye symptoms were analyzed after 3 and 7 weeks of therapy and reported no differences between the drugs. A second study found no difference between the agents in alleviating nasal or nonnasal symptoms.[84] Flunisolide 100 g twice/day and beclomethasone dipropionate 168 g twice/day were equally efficacious in a third trial.[85] Triamcinolone

Triamcinolone acetonide suspension for intranasal administration is available in metered-dose aerosol and aqueous pump spray; both supply 55 g of active compound/activation.[86, 87] Literature supports the idea that intranasal triamcinolone is superior to placebo for treatment of seasonal and perennial allergic rhinitis in adults and children aged 6 years and older.[86-91]

Recipients of triamcinolone aerosol and aqueous formulations at low dosages (110-220 g/day) experienced a reduction in allergic rhinitis symptoms within 1 day of starting therapy.[88-90] Another study of triamcinolone 440 g/day decreased symptoms within 10 hours compared with placebo.[91]

Relief of symptoms of seasonal or perennial allergic rhinitis by triamcinolone 220 g once/day, either aerosol or aqueous formulation, was similar to that produced by beclomethasone 84 g or 168 g twice/day over 3-12 weeks, or flunisolide 100 g twice/day for 4 weeks.[92-95] Triamcinolone 220 g/day and fluticasone 200 g/day similarly reduced overall symptoms of congestion, rhinorrhea, sneezing, and itching, with no significant difference in symptom scores.[96] Beclomethasone

Several intranasal corticosteroids discussed have efficacy equal or superior to beclomethasone for treatment of seasonal and perennial allergic rhinitis. Beclomethasone comes in two formulations, an aerosol and a spray, and is approved for use in adults and children aged 6 years and older. Each activation of the aerosol systems (Beconase, Vancenase, Vancenase Pockethaler) and the manual pump aqueous spray (Beconase AQ) delivers 42 g of drug.[97, 98] Vancenase AQ 84 g (double-strength) delivers 84 g of drug suspension by manual metered-spray pump.[99, 100]

The double-strength formulation was introduced to control symptoms with once/day intranasal dosing. According to a review of three clinical trials, when given once/day it was more effective than placebo and as effective as regular-strength beclomethasone dipropionate 42 g twice/day. Symptom improvement was seen and maintained within 2 days of starting therapy. Based on these studies, regular-strength and double-strength beclomethasone provide similar symptom relief; however, patient adherence may improve with once versus twice-daily administration.[100]

REFERENCE: Medscape Reference