Nasarel nasal solution 0.025%

Flunisolide, the active component of NASAREL nasal spray, is an anti-inflammatory glucocorticosteroid with the chemical name: 6(alpha)-fluoro-11(beta),16(alpha),17,21 tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone, hemihydrate. It has the following chemical structure:

Flunisolide is a white to creamy white crystalline powder with a molecular weight of 443.51 and molecular formula of C 24 H 31 FO 6 . It is soluble in acetone, sparingly soluble in chloroform, slightly soluble in methanol, and practically insoluble in water. It has a melting point of about 245°C. The octanol:water partition coefficient is 2.17 at neutral pH.

NASAREL is a metered dose manual pump spray unit containing 0.025% w/w flunisolide in an aqueous medium containing benzalkonium chloride, butylated hydroxytoluene, citric acid, edetate disodium, polyethylene glycol 400, polysorbate 20, propylene glycol, sodium citrate dihydrate, sorbitol and purified water. Sodium hydroxide and/or hydrochloric acid may be added to adjust the pH to a target of 5.2. Each 25 mL spray bottle contains 6.25 mg of flunisolide.

After initial priming (5 to 6 sprays), each spray of the pump spray unit delivers a metered spray of 100 mg formulation containing 29 mcg of flunisolide. The size of 99.5% of the droplets produced by the unit is greater than 8 microns. The contents of one nasal spray bottle delivers 200 sprays in addition to the priming sprays.

NASAREL is indicated for the management of the nasal symptoms of seasonal or perennial rhinitis.

The replacement of a systemic corticosteroid with topical corticoid can be accompanied by signs of adrenal insufficiency, and in addition some patients may experience symptoms of withdrawal, e.g., joint and/or muscular pain, lassitude and depression. Patients previously treated for prolonged periods with systemic corticosteroids and transferred to NASAREL should be carefully monitored to avoid acute adrenal insufficiency in response to stress.

Careful attention must also be given to patients who have associated asthma or other clinical conditions where too rapid a decrease in systemic corticosteroids may exacerbate their symptoms.

The use of NASAREL with systemic prednisone as alternate day therapy or with daily doses of less than 7.5 mg could increase the likelihood of hypothalamic-pituitary-adrenal axis suppression compared to a therapeutic dose of either one alone. Therefore, NASAREL treatment should be used with caution in patients already on prednisone regimens for any disease.

Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in nonimmune pediatric patients or adults on corticosteroids. In such pediatric patients 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 affects the risk of developing a disseminated infection is not known. The contribution of underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a nonimmune patient is exposed to chicken pox, 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 insert for complete VZIG and IG prescribing information). If chicken pox develops, treatment with antiviral agents may be considered.

General:   Intranasal corticosteroids may also cause a reduction in growth velocity when administered to pediatric patients (see PRECAUTIONS , Pediatric Use section).

Symptomatic relief may not occur in some patients for as long as 2 weeks. Although systemic effects are minimal at recommended doses, NASAREL should not be continued beyond 3 weeks in the absence of significant symptomatic improvement. In clinical studies with flunisolide administered intranasally, the development of localized infections of the nose and pharynx with Candida albicans has occurred only rarely. When such an infection develops it may require treatment with appropriate local therapy or discontinuance of treatment with NASAREL. Since there is no evidence that exceeding the maximum recommended dose of NASAREL is more effective, higher doses should be avoided. Patients should be advised to clear their nasal passages of secretions prior to use. NASAREL should not be used in the presence of untreated local infection involving the nasal mucosa. Flunisolide should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, fungal, bacterial or systemic viral infections or ocular herpes simplex.

As with other nasally inhaled corticosteroids, nasal septal perforations have been reported in rare instances with the use of flunisolide nasal sprays. Temporary or permanent loss of the sense of smell and taste have also been reported with the use of flunisolide nasal sprays.

Because of the inhibitory effect of corticosteroids on wound healing, a nasal corticosteroid should be used with caution in patients who have experienced recent nasal septal ulcers, recurrent epistaxis, nasal surgery or trauma, until healing has occurred.

Although systemic corticoid effects typical of Cushing's syndrome are minimal with recommended doses of topical steroids, this potential increases with excessive doses. If recommended doses are exceeded with long-term use, or if individuals are particularly sensitive, symptoms of hypercorticism could occur including suppression of hypothalamic-pituitary-adrenal function and/or retardation of growth in pediatric patients. Therefore, larger than recommended doses of NASAREL should be avoided.

Information for Patients:   Patients should use NASAREL at regular intervals since its effectiveness depends on its regular use. Patients should take the medication as directed and should not exceed the prescribed dose. A decrease in symptoms can be expected to occur within a few days of initiating therapy in allergic rhinitis patients. Patients should contact their physician if the condition worsens, if sneezing or nasal irritation occurs, or if symptoms do not improve by 3 weeks.

Persons taking immunosuppressant doses of corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay.

For proper use of this unit and to attain maximum improvement, the patient should read and follow the accompanying Patient Instructions carefully.

Carcinogenesis:  Long-term studies were conducted in mice and rats using oral administration to evaluate the carcinogenic potential of the drug. Flunisolide was administered to mice at doses of 5, 50 and 500 mcg/kg/day (15, 150 and 1500 mcg/m 2 respectively), and to rats at doses of 0.5, 1 and 2.5 mcg/kg/day (3.0, 5.9 and 14.8 mcg/m 2 respectively). There was an increase in the incidence of benign pulmonary adenomas in mice, but not in rats. Female rats receiving the highest oral dose had an increased incidence of mammary adenocarcinoma compared to control rats. An increased incidence of this tumor type has been reported for other corticosteroids.

Impairment of Fertility:  Female rats receiving high doses of flunisolide (200 mcg/kg/day or 1180 mcg/m 2 body surface area) showed some evidence of impaired fertility. Reproductive performance in the low (8 mcg/kg/day or 47.2 mcg/m 2 ) and mid-dose (40 mcg/kg/day or 236 mcg/m 2 ) groups was comparable to controls.

Pregnancy:  Pregnancy Category C. As with other corticosteroids, flunisolide has been shown to be teratogenic and fetotoxic in rabbits and rats at oral doses of 40 and 200 mcg/kg/day (480 mcg/m 2 and 1180 mcg/m 2 ) respectively. There are no adequate and well-controlled studies in pregnant women. Flunisolide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers:  It is not known whether this drug is excreted in human milk. Because other corticosteroids are excreted in human milk, caution should be exercised when flunisolide is administered to nursing women.

Pediatric Use:  NASAREL is not recommended for use in pediatric patients less than 6 years of age as safety and efficacy have not been assessed in this age group. For pediatric patients 6 years of age and over, recommended maximum daily doses should not be exceeded in order to minimize the risk of systemic corticoid effects, including potential growth retardation. (See INDIVIDUALIZATION OF DOSAGE and DOSAGE AND ADMINISTRATION .) Controlled clinical studies have shown that intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for "catch up" growth following discontinuation of treatment with intranasal corticosteroids has not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids, including NASAREL, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of safe and effective noncorticosteroid treatment alternatives. To minimize the systemic effects of intranasal corticosteroids, including NASAREL, each patient should be titrated to the lowest dose that effectively controls his/her symptoms.

Geriatric Use:  Clinical studies of NASAREL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

The adverse events rates listed below are based on symptoms spontaneously reported in multidose controlled clinical trials in comparing NASAREL and NASALIDE for treatment of allergic rhinitis. In patients receiving NASAREL the most common adverse events were transient aftertaste (17%) and transient nasal burning and stinging (13%). These symptoms did not usually interfere with treatment.

Adverse Event Rates for NASAREL:

Incidence Greater than 1% (probably causally related)

Respiratory: Nasal burning/stinging (13%), epistaxis * , nasal dryness, pharyngitis, cough increased

Gastrointestinal: Nausea

Special Senses: Aftertaste (17%)

Incidence 1% or Less (probably causally related)

Respiratory: Hoarseness

Special Senses: Abnormal sense of smell

Incidence 1% or Less (causal relationship unknown) **/*

Respiratory: Sinusitis

Adverse Event Rates for NASALIDE:

Incidence Greater than 1% (probably causally related)

Respiratory: Nasal burning/stinging (44%), epistaxis * , nasal dryness * , pharyngitis * , cough increased

Gastrointestinal: Nausea

Special Senses: Aftertaste (8%)

Incidence 1% or Less (probably causally related)

Respiratory: Hoarseness, nasal ulcer

Incidence 1% or Less (causal relationship unknown) **/*

Respiratory: Sinusitis

Cases of growth suppression have been reported for intranasal corticosteroids (including NASAREL) (see PRECAUTIONS , Pediatric Use section).