Aerobid

Indications : Asthma; Rhinitis, perennial allergic; Rhinitis, seasonal allergic

Pregnancy Category C

FDA Approved 1981 Sep

DRUG CLASS : Corticosteroids; Antiasthmatics; Corticosteroids-Inhalation/Nasal

BRAND NAMES : Aerobid (US); Aerobid-M (US); Bronalide (Bahamas, Barbados, Belize, Bermuda, Curacao, Guyana, Jamaica, Netherland-Antilles, Puerto-Rico, Surinam, Trinidad, Canada); Bronilide (France); Flunase (Israel); Gibiflu (Italy); Inhacort (Germany); Locasyn (Denmark); Lokilan (Norway); Lokilan Nasal (Finland, Sweden); Lunibron-A (Italy); Lunis (Italy); Nasalide (US); Nasarel (US); Rhinalar (Canada); Rhinalar Nasal Mist (Hong-Kong); Sanergal (Slovenia); Synaclyn (Japan); Syntaris (Bahamas, Barbados, Belize, Bermuda, Curacao, Guyana, Jamaica, Netherland-Antilles, Surinam, Trinidad, Germany, Austria, Hungary, Italy, England, Netherlands, Switzerland, Belgium, Portugal, Bulgaria, Czech-Republic, South-Africa, Bahrain, Kuwait); Syntaris Nasal Spray (Benin, Burkina-Faso, Ethiopia, Gambia, Ghana, Guinea, Ivory-Coast, Kenya, Liberia, Malawi, Mali, Mauritania, Mauritius, Morocco, Niger, Nigeria, Senegal, Seychelles, Sierra-Leone, Sudan, Tanzania, Tunia, Uganda, Zambia, Zimbabwe);
(International brand names outside U.S. in italics)

COST OF THERAPY : $ 621.96 (Asthma; Aerosol; 250 mcg/inh; 0.2/day; 365 days)

DESCRIPTION :

Nasal Solution

Flunisolide nasal solution is intended for administration as a spray to the nasal mucosa. Flunisolide, the active component of Flunisolide nasal solution, is an anti-inflammatory steroid with the chemical name: 6alpha-fluoro-11beta, 16alpha, 17, 21-tetrahydroxypregna-1,4-diene-3,20- dione cyclic 16,17-acetal with acetone (USAN).

Flunisolide is a white to creamy white crystalline powder with a molecular weight of 434.49. It is insoluble 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 approximately 5.3. It contains no fluorocarbons.

After priming the delivery system for Flunisolide, each actuation of the unit delivers a metered droplet spray containing approximately 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 at least 200 sprays.

Oral Inhaler

Flunisolide, the active component of Aerobid inhaler system, is an anti-inflammatory steroid having the chemical name 6alpha-fluoro-11beta, 16alpha, 17, 21-tetrahydroxypregna-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 soluble 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 (trichloromonofluoromethane, dichlorodifluoromethane and dichlorotetrafluoroethane) with sorbitan trioleate as a dispersing agent. Aerobid-M also contains menthol as a flavoring agent. Each activation delivers approximately 250 mcg of flunisolide to the patient. One Aerobid inhaler system is designed to deliver at least 100 metered inhalations.

CLINICAL PHARMACOLOGY :

Nasal Solution

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 which 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 Flunisolide, when used topically as recommended, is due to its direct local effect and not to an indirect effect through systemic absorption.

Following administration to flunisolide to man, approximately half of the administered dose is recovered in the urine and half in the stool; 65-70% of the dose recovered in urine is the primary metabolite, which has undergone loss of the 6alpha fluorine and addition of a 6beta 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 1-2 hours.

The effects of flunisolide on hypothalamic-pituitary-adrenal (HPA) axis function has been studied in volunteers. Flunisolide was administered intranasally as a spray in total doses over 7 times the recommended dose (2200 mcg equivalent to 88 sprays/days) in 2 subjects for 4 days, about 3 times the recommended dose (800 mcg, equivalent to 32 sprays/day) in 4 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, Flunisolide 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 children at doses ranging from 6 to 8 sprays (150-200 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.

The mechanisms responsible for the anti-inflammatory action of corticosteroids and for the activity of the aerosolized drug on the nasal mucosa are unknown.

Oral Inhaler

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-inflammatory 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 activation in this preparation is 10 times that per activation of 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 6beta-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 inhalation of 2.0 mg of flunisolide per day (the maximum recommended dose) of 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 leukocytes 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.

INDICATIONS AND USAGE :

Nasal Solution

Flunisolide is indicated for the topical treatment of the symptoms of seasonal or perennial or perennial rhinitis when effectiveness of or tolerance to conventional treatment is unsatisfactory.

Clinical studies have shown that improvement is based on a local effect rather than systemic absorption, and is usually apparent within a few days starting Flunisolide. However, symptomatic relief may not occur in some patients for as long as two weeks. Although systemic effects are minimal at recommended doses, Flunisolide should not be continued beyond 3 weeks in the absence of significant symptomatic improvement.

Flunisolide should not be used in the presence of untreated localized infection involving nasal mucosa.

Oral Inhaler

Flunisolide inhaler is indicated in the maintenance treatment of asthma as prophylactic therapy. Flunisolide is also indicated for asthma patients who require systemic corticosteroid administration, where adding flunisolide may reduce or eliminate the need for the systemic corticosteroids.

Flunisolide inhaler is NOT indicated for the relief of acute bronchospasm.

CONTRAINDICATIONS :

Nasal Solution

Hypersensitivity to any of the ingredients.

Oral Inhaler

Flunisolide inhaler is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.

Hypersensitivity to any of the ingredients of this preparation contraindicates its use.

WARNINGS :

Nasal Solution

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 e.g., joint and/or muscular pain, lassitude and depression. Patients previously treated for prolonged periods with systemic corticosteroids and transferred to flunisolide should be carefully monitored to avoid acute adrenal insufficiency in response to stress.

When transferred to Flunisolide, 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 Flunisolide with alternate-day prednisone systemic treatment could increase the likelihood of HPA suppression compared to a therapeutic dose of either one alone. Therefore, Flunisolide treatment should be used with caution in patients already on alternate-day prednisone regimens for any disease.

Oral Inhaler

Particular care is needed in patients who are transferred from systemically active corticosteroids to flunisolide inhaler because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to aerosol corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infections, particularly gastroenteritis. Although flunisolide Inhaler may provide control of asthmatic symptoms during these episodes, it does NOT provide the systemic steroid that is necessary for coping with emergencies.

During periods of stress or a severe asthmatic attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume systemic steroids (in larger doses) immediately and to contact their physician for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic steroids during periods of stress or a severe asthma attack. To assess the risk of adrenal insufficiency in emergency situations, routine tests of adrenal cortical function, including measurement of early morning cortisol levels, should be performed periodically in all patients. An early morning resting cortisol level may be accepted as normal if it falls at or near the normal mean level.

Localized infections with Candida albicans or Aspergillus niger have occurred in the mouth and pharynx and occasionally in the larynx. Positive cultures for oral Candida may be present in up to 34% of patients. Although the frequency of clinically apparent infection is considerably lower, these infections may require treatment with appropriate antifungal therapy or discontinuance of treatment with flunisolide inhaler.

Flunisolide inhaler is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm.

Patients should be instructed to contact their physician immediately when episodes of asthma that are not responsive to bronchodilators occur during the course of treatment. During such episodes, patients may require therapy with systemic corticosteroids. Theoretically, the use of inhaled corticosteroids with alternate day prednisone systemic treatment should be accompanied by more HPA suppression than a therapeutically equivalent regimen of either alone.

Transfer of patients from systemic steroid therapy to flunisolide inhaler may unmask allergic conditions previously suppressed by the systemic steroid therapy, e.g., rhinitis, conjunctivitis, and eczema.

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 non-immune children or adults on corticosteroids. In such children 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 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 monographs for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents may be considered.

PRECAUTIONS :

Nasal Solution
General

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 flunisolide.

Flunisolide is absorbed into the circulation. Use of excessive doses of Flunisolide may suppress hypothalamic-pituitary-adrenal function.

Flunisolide should be used with caution, if at all in patients with active quiescent tuberculosis infections of the respiratory tract or in treated 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 corticosteroid 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 the Patient

Patients should use Flunisolide 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 Flunisolide are fully manifested. One or two 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.

For the proper use of this unit and to attain maximum improvement, the patient should read and follow the accompanying Patient Instructions carefully. (Contact the manufacturer for this information).

Oral Inhaler
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), patients treated with 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 of 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 flunisolide 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 flunisolide in human subjects are still not fully known. In particular, the effects resulting from chronic use of flunisolide 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 flunisolide 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 the Patient

Since the relief from flunisolide 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 PACKAGE INSERT).

Patients whose systemic corticosteroids have been reduced or withdrawn should be instructed to carry a warning card indicating that 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.

CONTENTS UNDER PRESSURE.

Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F (49°C) may cause container to explode. Never throw container into fire or incinerator. Keep out of reach of children.

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.

Nasal Solution and Oral Inhaler
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 low (8 mcg/kg/day) and mid-dose (40 mcg/kg/day) groups was comparable to controls.

Pregnancy, Teratogenic Effects, 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 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.

ADVERSE REACTIONS :

Nasal Solution

Adverse reactions reported in controlled clinical trials and long-term open studies in 595 patients treated with Flunisolide 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 Flunisolide 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 Flunisolide 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 frequency of 5% or less were: nasal congestion, sneezing, epistaxis and/or bloody mucus, nasal irritation, watery eyes, sore throat, nausea and/or vomiting, headache and loss of sense of smell and taste. As is the case with other nasally inhaled corticosteroids, nasal septal perforations have been observed in rare instances.

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, i.e., Cushing’s syndrome, could occur.

Oral Inhaler

Adverse events reported in controlled clinical trials and long-term open studies in 514 patients treated with flunisolide are described below. Of those patients, 463 were treated for 3 months or longer, 407 for 6 months or longer, 287 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
Gastrointestinal : Diarrhea (10%), nausea and/or vomiting (25%), upset stomach (10%).
General : Flu (10%).
Mouth and Throat : Sore throat (20%).
Nervous system : Headache (25%).
Respiratory : Cold symptoms (15%), nasal congestion (15%), upper respiratory infection (25%).
Special Senses : Unpleasant tastes (10%).

Incidence 3-9%
Cardiovascular : Palpitations.
Gastrointestinal : Abdominal pain, heartburn.
General : Chest pain, decreased appetite, edema, fever.
Mouth and Throat : Candida infection.
Nervous System : Dizziness, irritability, nervousness, shakiness.
Reproductive : Menstrual disturbances.
Respiratory : Chest congestion, cough*, hoarseness, rhinitis, runny nose, sinus congestion, sinus drainage, sinus infection, sinusitis, sneezing, sputum, wheezing*.
Skin : Eczema, itching (pruritus), rash.
Special Senses : Ear infection, loss of smell or taste.

Incidence 1-3%
General : Chills, increased appetite and weight gain, malaise, peripheral edema, sweating, weakness.
Cardiovascular : Hypertension, tachycardia.
Gastrointestinal : Constipation, dyspepsia, gas.
Hemic/Lymph : Capillary fragility, enlarged lymph nodes.
Mouth and Throat : Dry throat, glossitis, mouth irritation, pharyngitis, phlegm, throat irritation.
Nervous System : Anxiety, depression, faintness, fatigue, hyperactivity, hypoactivity, insomnia, moodiness, numbness, vertigo.
Respiratory : Bronchitis, chest tightness*, dyspnea, epistaxis, head stuffiness, laryngitis, nasal irritation, pleurisy, pneumonia, sinus discomfort.
Skin : Acne, hives, or urticaria.
Special Senses : Blurred vision, earache, eye discomfort, eye infection.

Incidence Less Than 1% : Judged by investigators as possibly or probably drug related: Abdominal fullness, shortness of breath.

*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.

OVERDOSAGE :

Nasal Solution

IV flunisolide in animals at doses up to 4 mg/kg showed no effect. One spray bottle contains 6.25 mg of Flunisolide; therefore acute overdosage is unlikely.

DOSAGE AND ADMINISTRATION :

Nasal Solution

The therapeutic effects of corticosteroids, unlike those of decongestants, are not immediate. This should be explained to the patient in advance in order to ensure cooperation and continuation of treatment with the prescribed dosage regimen. Full therapeutic benefit requires regular use, and is usually evident within a few days. However, a longer period of therapy may be required may be required for some patients to achieve maximum benefit (up to 3 weeks). If no improvement is evidence by that time, flunisolide should not be continued.

Patients with blocked nasal passages should be encouraged to use a decongestant just before Flunisolide administration to ensure adequate penetration of the spray. Patients should also be advised to clear nasal passages of secretions prior to use.

Adults : The recommended starting dose of Flunisolide 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 3 times a day (total dose 300 mcg/day).

Children: 6-14 years : The recommended starting dose of Flunisolide is one spray (25 mcg) in each nostril 3 times a day or two sprays (50 mcg) in each nostril 2 times a day (total dose 150-200 mcg/day). Flunisolide is not recommended for use for children 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 children 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 the patients with perennial rhinitis may be maintained on as little as 1 spray in each nostril per day.

Store at controlled room temperature, 15°-30°C (59°-86°F).

Oral Inhaler

The 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 pediatric patients 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 flunisolide inhaler.

Patients Not Receiving Systemic Corticosteroids

Patients who require maintenance therapy of their asthma may benefit from treatment with flunisolide at the doses recommended above. In patients who respond to flunisolide, 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 Corticosteroids

Clinical studies have shown that flunisolide 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 flunisolide inhaler is started. Initially, flunisolide should be used concurrently with the patient’s usual maintenance dose of systemic corticosteroid. After approximately one week, gradual withdrawal 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 corticosteroid 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 severe asthma attack, transfer patients may require supplementary treatment with systemic corticosteroids.

PATIENT PACKAGE INSERT :

Oral Inhaler
Directions For Use

Before using your new flunisolide inhaler system, it is important that you read over the following simple instructions and familiarize yourself with the inhaler and its metal cartridge.

As your doctor has probably told you, the flunisolide inhaler system must be used for a few days before it begins working, and then should be used regularly to help reduce the frequency and severity of your asthma attacks. It is not a bronchodilator and will not provide relief during an actual asthmatic attack , but can cut down the number of bad attacks if used regularly every day.

  1. Before the first use, place the Aerobid metal cartridge inside the plastic container.
  2. Shake the inhaler system before each inhalation.
  3. Before each use, remove dustcap and inspect mouthpiece for foreign objects.
  4. Replace dustcap after each use.
  5. Breathe out as completely as possible.
  6. Hold the inhaler system upright and put plastic mouthpiece in your mouth, being sure to close your lips tightly around the mouthpiece.
  7. Breathe in slowly through your mouth. At the same time firmly press down on the metal cartridge with your index finger.
  8. Hold your breath as long as you can.
  9. While holding your breath, stop pressing on the cartridge and remove the mouthpiece from your mouth.
  10. If your doctor has prescribed two or more inhalations at each use, wait a minute to allow pressure to build up again in the metal canister, then repeat steps two through nine (2-9). Be sure to shake the inhaler system again before each inhalation.
  11. After the prescribed number of inhalations, rinse out your mouth thoroughly with water.
  12. Clean the inhaler system every few days. To do so, remove the metal cartridge, then rinse the plastic inhaler and cap with briskly running warm water. Dry thoroughly. Replace the cartridge and cap.

Note : If your mouth becomes sore or develops a rash, be sure to mention this to your physician, but do not stop using your inhaler system unless he tells you.

Warning : The contents of the metal cartridge are under pressure. Do not puncture. Do not use or store near heat or open flame. Exposure to temperature above 120°F (49°C) may cause cartridge to explode. Never throw cartridge into fire or incinerator. Use by children should always be supervised by an adult.

HOW SUPPLIED :

Note : The 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 enviornment by destryoing ozone in the upper atmosphere.

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