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Flunisolide
Flunisolide, the active component
of AEROBID Inhaler System, is an anti-inflammatory steroid having
the chemical name 6alpha-fluoro-l1beta,
16alpha, 17, 21-tetrahydroxy-pregna- 1, 4-diene-3, 20-dione cyclic-16,
17-acetal with acetone. Flunisolide is a white to creamy white crystalline powder with a molecular weight of 434.49. It is soluble in acetone, sparingly soluble in chloroform, slightly soluable in methanol, and practically insoluble in water. It has a melting point of about 245°C. AEROBID Inhaler is delivered in a metered-dose aerosol
system containing a microcrystalline
suspension of flunisolide
as the hemihydrate
in propellants (trichloro-monofluoromethane, dichlorodifluoromethane
and dlchlorotetraf uoroethane) with sorbitan trioleate as a dispersing
agent. AEROBID-M also contains menthol
as a flavoring agent. Each activation
delivers approximately 256 mcg
of flunisolide to the patient. One AEROBID Inhaler System is designed
to deliver at least
100 metered Inhalations.
Flunisolide has demonstrated marked anti-inflammatory and anti-allergic activity in classical test systems. It is a corticosteroid that is several hundred times more potent in animal anti-inflammator assays than the cortisol standard. The molar dose of each activation of flunisolide. In this preparation is approximately 2.5 to 7 times that of comparable inhaled corticosteroid products marketed for the same indication. The dose of flunisolide delivered per activatlon in this pre aeration is 10 times that per activation of Nasalide (flunisolide) nasal solution. Clinical studies have shown therapeutic activity on bronchial mucosa with minimal evidence of systemic activity at recommended doses. After oral inhalation of 1 mg flunisolide, total systemic availability was 40%. The flunisolide that is swallowed is rapidly and extensively converted to the S beta-OH metabolite and to water-soluble conjugates during the first pass through the liver. This offers a metabolic explanation for the low systemic activity of oral flunisolide itself since the metabolite has the low corticosteroid potency (on the order of the cortisol standard). The inhaled flunisolide absorbed through the bronchial tree is converted to the same metabolites. Repeated inhalatlon of 2.0 mg of flunisolide per day (the maximum recommended dose) for 14 days did not show accumulation of the drug in plasma.The plasma half-life of flunisolide is approximately 1.8 hours. The following observations relevant to systemic absorption were made in clinical studies. In one uncontrolled study a statistically significant decrease in responsiveness to metyrapone was noted in 15 adult steroid-independent patients treated with 2.0 mg of flunisolide per day (the maximum recommended dose) for 3 months. A small but statistically significant drop in eosinophils from 11.5% to 7.4% of total circulating leucocytes was noted in another study in children who were not taking oral corticosteroids simultaneously. A 5% incidence of menstrual disturbances was reported during open studies, in which there were no control groups for comparison. Aerosol administration of flunisolide 2.0 mg twice daily for one week to 6 healthy male subjects revealed neither suppression of adrenal function as measured by early morning cortisol levels nor impairment of HPA axis function as determined by insulin hypoglycemia tests. Controlled clinical studies have included over 500 patients with asthma, among them 150 children age 6 and over. More than 120 patients have been treated in open trials for two years or more. No significant adrenal suppression attributed to flunisolide was seen in these studies. Significant decreases of systemic
steroid dosages have
been possible in flunisolide-treated patients. Recommended doses
of flunisolide appear to be the therapeutic
equivalent of an
average of 10 mg/day
of oral prednisone. Asthma
patients have had further symptomatic
improvement with flunisolide treatment even while reducing concomitant
medication.
AEROBID (flunisolide) Inhaler is indicated in the maintenance treatment of asthma as prophylactic therapy. AEROBID is also indicated for asthma patients who require systemic corticosteroid administration, where adding AEROBID may reduce or eliminate the need for the systemic corticosteroids. AEROBID Inhaler is NOT indicated for the relief of acute bronchospasm.
The AEROBID (flunisolide) Inhaler System is for oral inhalation only. Adults: The recommended starting dose is 2 inhalations twice daily, morning and evening, for a total daily dose of 1 mg. The maximum daily dose should not exceed 4 inhalations twice a day for a total daily dose of 2 mg. When the drug is used chronically at 2 mg/day, patients should be monitored periodically for effects on the hypothalamic-pituitary-adrenal (HPA) axis. Pediatric Patients For children and adolescents 6-15 years of age, two inhalations may be administered twice daily for a total daily dose of 1 mg. Higher doses have not been studied. Insufficient information is available to warrant use in children under age 6. With chronic use, pediatric patients should be monitored for growth as well as for effects on the HPA axis. Rinsing the mouth after inhalation is advised. Different considerations must be given to the following groups of patients in order to obtain the full therapeutic benefit of AEROBID (flunisolide) Inhaler. Patients Not Receiving Systemic Corticosterolds Patients who require maintenance therapy of their asthma may benefit from treatment with AEROBID at the doses recommended above. In patients who respond to AEROBID, improvement in pulmonary function is usually apparent within one to four weeks after the start of therapy. Once the desired effect is achieved, consideration should be given to tapering to the lowest effective dose. Patients Maintained on Systemic Corticosterolds Clinical studies have shown that AEROBID may be effective in the management of asthmatics dependent or maintained on systemic corticosteroids and may permit replacement or significant reduction in the dosage of systemic corticosteroids. The patient’s asthma should be reasonably stable before treatment with AEROBID is started. Initially, AEROBID should be used concurrently with the patient’s usual maintenance dose of systemic corticosteroid. After approximately one week, gradual with-drawal of the systemic corticosteroid is started by reducing the daily or alternate daily dose. Reductions may be made after an interval of one or two weeks, depending on the response of the patient. A slow rate of withdrawal is strongly recommended. Generally, these decrements should not exceed 2.5 mg of prednisone or its equivalent. During withdrawal, some patients may experience symptoms of systemic cortico-steroid withdrawal; e.g. joint and/or muscular pain, lassitude and depression, despite maintenance or even improvement in pulmonary function. Such patients should be encouraged to continue with the inhaler but should be monitored for objective signs of adrenal insufficiency. If evidence of adrenal insufficiency occurs, the systemic corticosteroid doses should be increased temporarily and thereafter withdrawal should continue more slowly. During periods of stress or a severe asthma attack, transfer patients may require supplementary treatment with systemic corticosteroids. HOW SUPPLIED AEROBID (flunisolide) Inhaler Systems are available in canisters of 100 metered inhalations. “Note: The indented statement below is required by the Federal government’s Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFC’s).” WARNING: Contains trichloromonofluoromethane, dichlorodifluoromethane and dichlorotetrafluoroethane, substances which harm public health and environment by destroying ozone in the upper atmosphere. A notice similar to the above WARNING has been placed in the information for the patient of this product pursuant to EPA regulations.* Caution: Federal Law prohibits dispensing without prescription.
Adverse events reported in controlled clinical trials and long-term open studies in 514 patients treated with AEROBID (flunisolide) are described below. Of those patients; 463 were treated for 3 months or longer, 407 for 6 months or longer, 267 for 1 year or longer, and 122 for 2 years or longer. Musculoskeletal reactions were reported in 35% of steroid-dependent patients in whom the dose of oral steroid was being tapered. This is a well-known effect of steroid withdrawal. Incidence 10% or greater:
Incidence 3-9%:
Incidence l-3%:
Incidence less than 1% judged by investigators as possibly or probably drug related:
*The incidences as shown of cough, wheezing, and chest tightness were judged by investigators to be possibly or probably drug related. In placebo-controlled trials, the overall incidences of these adverse events (regardless of investigators’ judgement of drug relationship) were similar for drug and placebo-treated groups. They may be related to the vehicle or delivery system.
No information provided.
General Because of the relatively high molar dose of flunisolide per activation in this preparation, and because of the evidence suggesting higher levels of systemic absorption with flunisolide than with other comparable inhaled corticosteroids (see CLINICAL PHARMACOLOGY section), patients treated with AEROBID (flunisolide) should be observed carefully for any evidence of systemic corticosteroid effect, including suppression of bone growth in children. Particular care should be taken in observing patients post-operatively or during periods of stress for evidence of a decrease in adrenal function. During withdrawal from oral steroids, some patients may experience symptoms of systemically active steroid withdrawal, e.g. joint and/or muscular pain, lassitude and depression, despite maintenance or even improvement of respiratory function. (See DOSAGE AND ADMINISTRATION for details.) In responsive patients, flunisolide may permit control of asthmatic symptoms without suppression of HPA function. Since flunisolide is absorbed into the circulation and can be systemically active, the beneficial effects of AEROBID Inhaler in minimizing or preventing HPA dysfunction may be expected only when recommended dosages are not exceeded. The long-term local and systemic effects of AEROBID (flunisolide) in human subjects are still not fully known. In particular, the effects resulting from chronic use of AEROBID on developmental or immunologic processes in the mouth, pharynx, trachea, and lung are unknown. Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial, parasitic or viral infections; or ocular herpes simplex. Pulmonary infiltrates with eosinophilia may occur in patients on AEROBID Inhaler therapy. Although it is possible that in some patients this state may become manifest because of systemic steroid withdrawal when inhalational steroids are administered, a causative role for the drug and/or its vehicle cannot be ruled out. Information for Patients Since the relief from AEROBID Inhaler depends on its regular use and on proper inhalation technique, patients must be instructed to take inhalations at regular intervals. They should also be instructed in the correct method of use. (See Patient Instruction Leaflet.) Patients whose systemic corticosteroids have been reduced or withdrawn should be instructed to carry a warning card indicating they may need supplemental systemic steroids during periods of stress or a severe asthmatic attack that is not responsive to bronchodilators. Persons 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. An illustrated leaflet of patient instructions for proper use accompanies each AEROBID Inhaler System. CONTENTS UNDER PRESSURE Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F (49%) may cause container to explode. Never throw container into fire or incinerator. Keep out of reach of children. Carcinogenesis Long-term studies were conducted in mice and rats using oral administration to evaluate the carcinogenic potential of the drug. There was an increase in the incidence of 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) showed some evidence of impaired fertility. Reproductive performance in the low- (6 mcg/kg/day) and mid-dose (40 mcg/kg/day) groups was comparable to controls. Pregnancy Pregnancy Category C. As with other corticosteroids, flunisolide has been shown to be teratogenic in rabbits and rats at doses of 40 and 200 mcg/kg/day respectively. It was also fetotoxic in these animal reproductive studies. 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 Safety and effectiveness
have not been established in children below the age
of 6. Oral corticoids have been shown to cause
growth suppression in
children and adolescents, particularly with higher doses over extended
periods. If a child or
adolescent on any
corticoid appears
to have growth suppression, the possibility that they are particularly
sensitive to this
effect of steroids should be considered.
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