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NASALIDE® (flunisolide) nasal spray is intended for administration as a spray to the nasal mucosa. Flunisolide, the active component of NASALIDE nasal spray, is an anti-inflammatory steroid 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 (USAN).
It has the following chemical structure:
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Flunisolide is a white to creamy white crystalline powder with a molecular weight of 434.49 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.
Each 25 mL spray bottle contains flunisolide 6.25 mg (0.25 mg/mL) in a solution of propylene glycol, polyethylene glycol 3350, citric acid, sodium citrate, butylated hydroxyanisole, edetate disodium, benzalkonium chloride and purified water, with NaOH and/or HCl added to adjust the pH to a target of 5.3.
After initial priming (5 to 6 sprays), each spray of the unit delivers a metered droplet of 100 mg formulation spray containing 25 mcg of flunisolide. The size of the droplets produced by the unit is in excess of 8 microns to facilitate deposition on the nasal mucosa. The contents of one nasal spray bottle deliver 200 sprays.
Flunisolide has demonstrated potent glucocorticoid and weak mineralocorticoid activity in classical animal test systems. As a glucocorticoid it is several hundred times more potent than the cortisol standard. Clinical studies with flunisolide have shown therapeutic activity on nasal mucous membranes with minimal evidence of systemic activity at the recommended doses.
A study in approximately 100 patients that compared the recommended dose of flunisolide nasal solution with an oral dose providing equivalent systemic amounts of flunisolide has shown that the clinical effectiveness of NASALIDE, when used topically as recommended, is due to its direct local effect and not to an indirect effect through systemic absorption.
Following administration of flunisolide to man, approximately half of the administered dose is recovered in the urine and half in the stool; 65% to 70% of the dose recovered in urine is the primary metabolite, which has undergone loss of the 6(alpha) fluorine and addition of a 6(beta) hydroxy group. Flunisolide is well absorbed but is rapidly converted by the liver to the much less active primary metabolite and to glucuronate and/or sulfate conjugates. Because of first-pass liver metabolism, only 20% of the flunisolide reaches the systemic circulation when it is given orally whereas 50% of the flunisolide administered intranasally reaches the systemic circulation unmetabolized. The plasma half-life of flunisolide is 1 to 2 hours.
The effects of flunisolide on hypothalamic-pituitary-adrenal (HPA) axis function have been studied in adult volunteers. NASALIDE was administered intranasally as a spray in total doses over 7 times the recommended dose (2200 mcg, equivalent to 88 sprays/day) in 2 subjects for 4 days, about 3 times the recommended dose (800 mcg, equivalent to 32 sprays/day) in 4 subjects for 4 days, and over twice the recommended dose (700 mcg, equivalent to 28 sprays/day) in 6 subjects for 10 days. Early morning plasma cortisol concentrations and 24-hour urinary 17-ketogenic steroids were measured daily. There was evidence of decreased endogenous cortisol production at all three doses.
In controlled studies, NASALIDE was found to be effective in reducing symptoms of stuffy nose, runny nose and sneezing in most patients. These controlled clinical studies have been conducted in 488 adult patients at doses ranging from 8 to 16 sprays (200-400 mcg) per day and 127 pediatric patients at doses ranging from 6 to 8 sprays (150 to 200 mcg) per day for periods as long as 3 months. In 170 patients who had cortisol levels evaluated at baseline and after 3 months or more of flunisolide treatment, there was no unequivocal flunisolide-related depression of plasma cortisol levels.
Clinical studies have shown that improvement is usually apparent within a few days after starting NASALIDE.
The mechanisms responsible for the anti-inflammatory action of corticosteroids and for the activity of the aerosolized drug on the nasal mucosa are unknown.
NASALIDE is indicated for the nasal treatment of the symptoms of seasonal or perennial rhinitis.
NASALIDE should not be used in the presence of untreated localized infection involving nasal mucosa.
Hypersensitivity to any of the ingredients.
The replacement of a systemic corticosteroid with a topical corticoid can be accompanied by signs of adrenal insufficiency, and in addition some patients may experience symptoms of withdrawal, eg, joint and/or muscular pain, lassitude and depression. Patients previously treated for prolonged periods with systemic corticosteroids and transferred to NASALIDE should be carefully monitored to avoid acute adrenal insufficiency in response to stress.
When transferred to NASALIDE, careful attention must be given to patients previously treated for prolonged periods with systemic corticosteroids. This is particularly important in those patients who have associated asthma or other clinical conditions, where too rapid a decrease in systemic corticosteroids may cause a severe exacerbation of their symptoms.
The use of NASALIDE with alternate-day prednisone systemic treatment could increase the likelihood of HPA axis suppression compared to a therapeutic dose of either one alone. Therefore, NASALIDE treatment should be used with caution in patients already on alternate-day prednisone regimens for any disease.
Persons who are on drugs that 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 the 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: Symptomatic relief may not occur in some patients for as long as 2 weeks. Although systemic effects are minimal at recommended doses, NASALIDE 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 have occurred only rarely. When such an infection develops it may require treatment with appropriate local therapy or discontinuance of treatment with NASALIDE.
Flunisolide is absorbed into the circulation. Use of excessive doses of NASALIDE may suppress HPA axis function.
Flunisolide should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract or in untreated fungal, bacterial or systemic viral infections or ocular herpes simplex.
Because of the inhibitory effect of corticosteroids on wound healing, in patients who have experienced recent nasal septal ulcers, recurrent epistaxis, nasal surgery or trauma, a nasal corticosteroids should be used with caution until healing has occurred.
Although systemic effects have been minimal with recommended doses, this potential increases with excessive dosages. Therefore, larger than recommended doses should be avoided.
Information for Patients: Patients should use NASALIDE at regular intervals since its effectiveness depends on its regular use. The patient should take the medication as directed. It is not acutely effective and the prescribed dosage should not be increased. Instead, nasal vasoconstrictors or oral antihistamines may be needed until the effects of NASALIDE are fully manifested. One to 2 weeks may pass before full relief is obtained. The patient should contact the physician if symptoms do not improve, or if the condition worsens, or if sneezing or nasal irritation occurs.
Person who are on 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 the proper use of this unit and to attain maximum improvement, the patient should read and follow the accompanying patient leaflet of instructions carefully.
Patients should be advised to clear their nasal passages of secretions prior to use.
Carcinogenesis, Mutagenesis, Impairment of Fertility: In mice, flunisolide at an oral dose of 500 mcg/kg/day (approximately 6 times the maximum recommended daily intranasal dose in adults and children on a mg/m 2 basis) for 21 months was negative for carcinogenic effects. In rats, administration of flunisolide at an oral dose of 2.5 mcg/kg/day (less than the maximum recommended daily intranasal dose in adults and children on a mg/m 2 basis) for 24 months resulted in an increased incidence of mammary gland adenoma and islet cell adenoma of the pancreas in females. There were no significant increases in the incidence of any tumor type in rats at an oral dose of 1.0 mcg/kg (less than the maximum recommended daily intranasal dose in adults and children on a mg/m 2 basis
Flunisolide showed no mutagenic activity in in vitro test systems including the Ames Assay and the Rec-Assay, and no clastogenic activity in either the in vitro chromosomal aberration assay in Chinese hamster lung fibroblast cells or the in vivo mouse bone marrow chromosomal aberration assay.
Flunisolide, at an oral dose of 200 mcg/kg/day (approximately 4 times the maximum recommended daily intranasal dose in adults on a mg/m 2 basis) produced impaired fertility in female rats, but was devoid of such effects at oral doses less than or equal to 40 mcg/kg/day (approximately equal to the maximum recommended daily intranasal dose in adults on a mg/m 2 basis
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 respectively. (approximately 2 and 4 times, respectively, the maximum recommended daily intranasal dose in adults on a mg/m 2 basis). 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: NASALIDE is not recommended for use in pediatric patients less than 6 years of age as safety and efficacy, including possible adverse effects on growth, have not been assessed in this age group.
Adverse reactions reported in controlled clinical trials and long-term open studies in 595 patients treated with NASALIDE are described below. Of these patients, 409 were treated for 3 months or longer, 323 for 6 months or longer, 259 for 1 year or longer and 91 for 2 years or longer.
In general, side effects elicited in the clinical studies have been primarily associated with the nasal mucous membranes. The most frequent complaints were those of mild transient nasal burning and stinging, which were reported in approximately 45% of the patients treated with NASALIDE in placebo-controlled and long-term studies. These complaints do not usually interfere with treatment; in only 3% of patients was it necessary to decrease dosage or stop treatment because of these symptoms. Approximately the same incidence of mild transient nasal burning and stinging was reported in patients on placebo as was reported in patients treated with NASALIDE in controlled studies, implying that these complaints may be related to the vehicle or the delivery system. The incidence of complaints of nasal burning and stinging decreased with increasing duration of treatment.
Other side effects reported at a frequency of 5% or less were: nasal congestion, sneezing, epistaxis and/or bloody mucus, nasal irritation, watery eyes, sore throat, nausea and/or vomiting and headaches. As with other nasally inhaled corticosteroids, nasal septal perforations have been reported in rare instances with the use of flunisolide nasal solutions. Temporary or permanent loss of the sense of smell and taste have also been reported with the use of flunisolide nasal solutions.
Systemic corticosteroid side effects were not reported during the controlled clinical trials. If recommended doses are exceeded, or if individuals are particularly sensitive, symptoms of hypercorticism, ie, Cushing' syndrome, could occur.
Flunisolide, infused intravenously, at doses up to 4 mg/kg in mice, rats and dogs (approximately 45, 300 and 90 times, respectively, the maximum recommended daily intranasal dose in adults and children on a mg/m 2 basis) was without lethality.
Adults: The recommended starting dose of NASALIDE is 2 sprays (50 mcg) in each nostril 2 times a day (total dose 200 mcg/day). If needed, this dose may be increased to 2 sprays in each nostril times a day (total dose 300 mcg/day).
Pediatric Patients 6 to 14 years: The recommended starting dose of NASALIDE is 1 spray (25 mcg) in each nostril 3 times a day or 2 sprays (50 mcg) in each nostril 2 times a day (total dose 150 to 200 mcg/day). NASALIDE is not recommended for use in pediatric patients less than 6 years of age as safety and efficacy studies, including possible adverse effects on growth, have not been conducted.
Maximum total daily doses should not exceed 8 sprays in each nostril for adults (total dose 400 mcg/day) and 4 sprays in each nostril for pediatric patients under 14 years of age (total dose 200 mcg/day). Since there is no evidence that exceeding the maximum recommended dosage is more effective and increased systemic absorption would occur, higher doses should be avoided.
After the desired clinical effect is obtained, the maintenance dose should be reduced to the smallest amount necessary to control the symptoms. Approximately 15% of patients with perennial rhinitis may be maintained on as little as 1 spray in each nostril per day.
For priming and repriming the nasal spray unit after storage: The patient should remove the green dust cover. Put two fingers on "shoulders" of preset pump unit, and place thumb on bottom of bottle. Push bottle with thumb FIRMLY and QUICKLY 5-6 times or until a fine spray appears. Now your preset pump is primed. The patient must prime the preset pump unit again if it has not been used for 5 days or more, or if it has been disassembled for cleaning.
A patient leaflet of instructions accompanies each package of NASALIDE Nasal Spray.
Do not spray in eyes.
NASALIDE is contained in a metered-dose, manual pump spray unit. Each 25 mL NASALIDE nasal spray white, HDPE bottle (NDC 51479-038-25) contains 6.25 mg (0.25 mg/mL), 200 sprays of flunisolide and is supplied in a nasal pump dispenser with green dust cover cap and with a patient leaflet of instructions.
Store at 15°-30°C (59°-86°F).
CONTENTS MADE IN CANADA
Rx only.
Revised: May, 2000
Manufactured for:
Dura Pharmaceuticals, Inc.
San Diego, CA 92121
Manufactured by:
PATHEON INC.
Mississauga, Ontario,
CANADA L5N 7K9
NIDE001C00
IN-5048/S
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