Flunisolide (inhalation)

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# Overview
Flunisolide (inhalation) is a glucocorticoid that is FDA approved for the prophylaxis of asthma.   Common adverse reactions include vomiting, rhinitis, headache and increased cough.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
Flunisolide is indicated for the maintenance treatment of asthma as prophylactic therapy in adult and pediatric patients 6 years of age and older. Flunisolide is also indicated for asthma patients requiring oral corticosteroid therapy, where adding Flunisolide may reduce or eliminate the need for oral corticosteroids.
- Dosage:
- Starting Dose: 160 mcg twice daily
- Highest Recommended Dose: 320 mcg twice daily

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Flunisolide in adult patients.

### NonGuideline-Supported Use
- Eosinophilic nonallergic rhinitis
- Sinusitis

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
Flunisolide is indicated for the maintenance treatment of asthma as prophylactic therapy in adult and pediatric patients 6 years of age and older. Flunisolide is also indicated for asthma patients requiring oral corticosteroid therapy, where adding Flunisolide may reduce or eliminate the need for oral corticosteroids.
- Adolescents 12 years of age and older dosage:
- Starting Dose: 160 mcg twice daily
- Highest Recommended Dose: 320 mcg twice daily
- Children 6 to 11 years dosage:
Starting Dose: 80 mcg twice daily
- Highest Recommended Dose: 160 mcg twice daily

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Flunisolide in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Flunisolide in pediatric patients.

# Contraindications
- Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.

# Warnings
In clinical studies with flunisolide, localized infections with Candida albicans or Aspergillus niger have occurred in the mouth and pharynx and occasionally in the larynx. If oropharyngeal candidiasis develops, treat with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing with flunisolide therapy, but at times therapy with flunisolide may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised.
flunisolide is not a bronchodilator and is not indicated for rapid relief of bronchospasm. Instruct patients to contact their physician immediately when episodes of asthma that are not responsive to bronchodilators occur during the course of treatment with flunisolide. During such episodes, patients may require therapy with systemic corticosteroids.
Patients who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox 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 or been properly immunized, 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 prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella-zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.
Because of the potential for worsening infections, use inhaled corticosteroids with caution, if at all, in patients with untreated active or quiescent tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial, parasitic or viral infections; or ocular herpes simplex.
Particular care is needed in patients who are transferred from systemically active corticosteroids to flunisolide because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.
Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery or infections (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although flunisolide may provide control of asthmatic symptoms during these episodes, in recommended doses it supplies less than the physiologic amounts of glucocorticoid (cortisol) systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these 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 immediately and to contact their physician for further instruction. Instruct these patients to carry a warning card indicating that they may need supplementary systemic steroids during periods of stress or a severe asthma attack.
Wean patients requiring oral corticosteroids slowly from systemic corticosteroid use after transferring to flunisolide. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg/day on a weekly basis. Lung function (forced expiratory volume in one second  or morning peak expiratory flow rate ), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, observe patients for signs and symptoms of adrenal insufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.
Transfer of patients from systemic corticosteroid therapy to flunisolide may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy, e.g. rhinitis, conjunctivitis, eczema, arthritis, and eosinophilic conditions.
During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal, e.g., joint or muscular pain, lassitude and depression, despite maintenance or even improvement of respiratory function.
In responsive patients, flunisolide may permit control of asthmatic symptoms with less suppression of HPA axis function than therapeutically equivalent oral doses of prednisone. Since flunisolide is absorbed into the circulation and can be systemically active, the beneficial effects of flunisolide in minimizing or preventing HPA axis dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing flunisolide.
Because of the possibility of systemic absorption of inhaled corticosteroids, observe patients treated with flunisolide carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients post-operatively or during periods of stress for evidence of inadequate adrenal response.
It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear in a small number of patients, particularly at higher doses. If such changes occur, reduce the flunisolide dose slowly, consistent with accepted procedures for management of asthma symptoms and for tapering of systemic corticosteroids.
Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids, including flunisolide. The clinical significance of small changes in BMD with regard to long-term outcomes is unknown. Monitor patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants and corticosteroids) and treat with established standards of care.
Orally inhaled corticosteroids, including flunisolide, may cause a reduction in growth velocity when administered to pediatric patients . Monitor the growth of children and adolescents receiving flunisolide. To minimize the systemic effects of orally inhaled corticosteroids, including flunisolide, each titrate each patient to his/her lowest effective dose.
Glaucoma, increased intraocular pressure, and cataracts have been reported in patients following the long-term administration of inhaled corticosteroids, including flunisolide. Monitor patients closely, especially patients with a change in vision or with a history of increased intraocular pressure, glaucoma, or cataracts.
As with other inhaled asthma medications, bronchospasm may occur with an immediate increase in wheezing after dosing. If bronchospasm occurs following dosing with flunisolide, treat immediately with a fast-acting inhaled bronchodilator. Discontinue treatment with flunisolide immediately and institute alternative therapy.

# Adverse Reactions

## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The following table shows the adverse reactions that were reported in patients previously receiving bronchodilators and/or orally inhaled corticosteroids in two double-blind, placebo- controlled US clinical trials, in which 519 adult and pediatric patients age 4-78 years (279 males and 240 females) were treated with the flunisolide (80 mcg to 320 mcg twice daily for 12 weeks) or placebo. The mean duration of exposure was 76.7, 78.2, 80.5, and 69.4 days for flunisolide 80 mcg, 160 mcg, 320 mcg, and placebo, all dosed twice daily, respectively. The table includes all reactions that occurred at a rate of >3% in any flunisolide group. In considering these data, the increased average duration of exposure for flunisolide patients should be taken into account, compared with placebo-treated patients.
The following other adverse reactions occurred in patients in these clinical trials using flunisolide with an incidence of 1 to 3% and were more common in flunisolide than in the placebo group.
- Body As A Whole: abdominal pain, chest pain, infection, neck pain
- Digestive System: diarrhea, gastroenteritis, nausea, oral moniliasis
- Metabolic And Nutritional Disorders: edema
- Musculoskeletal System: myalgia
- Nervous System: dizziness, insomnia, migraine
- Respiratory System: bronchitis, laryngitis, voice alteration
- Skin And Appendages: erythema multiforme
- Special Senses: conjunctivitis, ear pain, taste perversion
- Urogenital System: dysmenorrhea, vaginitis
Two 52-week open label safety trials of flunisolide were conducted in 162 asthma patients 12 to 60 years of age and in 152 asthma patients 4 to 11 years of age. The adverse reaction profile exhibited in these trials was similar to that seen in the two 12-week studies.
The following additional adverse reactions were derived from clinical trials conducted with flunisolide CFC inhalation aerosol with a frequency of 1% and not described above:
- Body as a Whole: flu, decreased appetite, chills, increased appetite, weight gain, malaise, peripheral edema, sweating, weakness
- Gastrointestinal System: upset stomach, heartburn, constipation, gas, abdominal fullness
- Cardiovascular System: palpitations, hypertension, tachycardia
- Nervous System: headache, irritability, shakiness, anxiety, depression, faintness, fatigue, hyperactivity, hypoactivity, moodiness, numbness, vertigo
- Respiratory System: cold symptoms, nasal congestion, upper respiratory tract infection, chest congestion, hoarseness, runny nose, sinus congestion, sinus drainage, sinus infection, sneezing, sputum, wheezing, chest tightness, bronchospasm, dyspnea, head stuffiness, nasal irritation, pleurisy, pneumonia, sinus discomfort
- Skin and Appendages: eczema, pruritus, acne, urticaria
- Special Senses: loss of smell, loss of taste, ear infection, blurred vision, eye discomfort, eye infection
- Hemic and Lymph: capillary fragility, enlarged lymph nodes
- Mouth and Throat: sore throat, dry throat, glossitis, mouth irritation, phlegm, throat irritation

## Postmarketing Experience
There is limited information regarding Flunisolide (inhalation) Postmarketing Experience in the drug label.

# Drug Interactions
There is limited information regarding Flunisolide (inhalation) Drug Interactions in the drug label.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well-controlled studies of flunisolide in pregnant women. flunisolide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
As with other corticosteroids, flunisolide has been shown to be teratogenic and fetotoxic in rabbits and rats at approximately 1 and 3 times the maximum recommended daily inhalation dose on a mg/m2 basis, respectively (doses of 40 and 200 mcg/kg/day, respectively).
Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiological, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans.
Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.
Pregnancy Category (AUS): B3
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Flunisolide (inhalation) in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Flunisolide (inhalation) during labor and delivery.

### Nursing Mothers
It is not known whether flunisolide 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
The safety and effectiveness of flunisolide has been studied in children 4- 17 years of age. In clinical studies, the efficacy of flunisolide was not established in children 4-5 years of age, although the adverse reaction profile observed in patients exposed to flunisolide was similar between the 4-5 year age group (n=21), the 6-11 year age group (n=210), the 12-17 year age group (n=30), and those patients 18 years of age and older (n=258). The safety and effectiveness of flunisolide has not been studied in patients less than 4 years of age.
Controlled clinical studies have shown that orally inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. In these studies, the mean reduction in growth velocity was approximately one cm per year (range 0.3 to 1.8 cm per year) and appears to depend upon the dose and duration of exposure. This effect was 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 orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for "catch up" growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. The growth of pediatric patients receiving orally inhaled corticosteroids, including flunisolide, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the risks/benefits of treatment alternatives. To minimize the systemic effects of orally inhaled corticosteroids, including flunisolide, each patient should be titrated to the lowest dose that effectively controls his/her symptoms.
The potential effect of AEROSPAN on growth rates in children was assessed in a 52 week randomized, placebo controlled study conducted in 242 prepubescent children age 4 to 9.5 years (145 males, 97 females) with mild persistent asthma. Treatment groups were AEROSPAN 160 mcg twice daily and placebo. Growth velocity was estimated for each patient using the slope of the linear regression of height over time using observed data in the intent to treat population who had at least 3 height measurements. The mean growth velocities were 6.19 cm/year in the placebo group and 6.01 cm/year in the AEROSPAN treated group (difference from placebo -0.17 cm/year; 95% CI: -0.58, 0.24).

### Geriatic Use
Clinical studies of flunisolide included 21 patients 65 to 78 years of age exposed to flunisolide. These studies did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from 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.

### Gender
There were no gender differences for flunisolide after single and multiple dose administration of the flunisolide.

### Race
There is no FDA guidance on the use of Flunisolide (inhalation) with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Flunisolide (inhalation) in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Flunisolide (inhalation) in patients with hepatic impairment.

### Females of Reproductive Potential and Males
Studies on the effects of flunisolide on fertility in female rats showed that flunisolide, at an oral dose of 200 mcg/kg/day (approximately 3 times MRDID on a mg/m2 basis) impaired fertility, but was devoid of such effects at doses up to 40 mcg/kg/day (less than MRDID on a mg/m2 basis).

### Immunocompromised Patients
There is no FDA guidance one the use of Flunisolide (inhalation) in patients who are immunocompromised.

# Administration and Monitoring

### Administration
Oral inhalation

### Monitoring
There is limited information regarding Flunisolide (inhalation) Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Flunisolide (inhalation) and IV administrations.

# Overdosage
In a double-blind, placebo-controlled study, 18 mg of flunisolide was administered via the CFC formulation over a three-hour period (nine times the maximum labeled daily dose) in 94 patients with acute asthma, and no clinically deleterious effects were observed.

# Pharmacology

## Mechanism of Action
Flunisolide has demonstrated marked anti-inflammatory activity in classical test systems. It is a corticosteroid that is several hundred times more potent than cortisol in animal anti-inflammatory assays, and several hundred times more potent than dexamethasone in anti-inflammatory effect as determined by the McKenzie skin blanching test. The clinical significance of these findings is unknown.
The precise mechanism of corticosteroid action is unknown. Airway inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of anti-inflammatory effects, inhibiting both inflammatory cells (e.g. mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and release of inflammatory mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic and non-allergic-mediated inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.

## Structure
Flunisolide chemical structure is:

## Pharmacodynamics
Dose finding for flunisolide was based on comparability of systemic exposure to flunisolide CFC inhalation aerosol. The effect of flunisolide CFC inhalation aerosol and flunisolide on pharmacokinetics and 12-hour plasma cortisol levels was investigated in two studies. In both studies, the Cmax and AUC of flunisolide, 6-OH flunisolide, and 12-hour plasma cortisol measurements were comparable for 1000 mcg of flunisolide CFC inhalation aerosol and 320 mcg of flunisolide. The first was a parallel arm study in 31 subjects. Pharmacokinetics and plasma cortisol levels were determined after single and multiple doses of flunisolide CFC inhalation aerosol 1000 g and flunisolide 160 g or 320 g administered twice daily for 13.5 days. At steady state, flunisolide mean peak plasma concentrations from flunisolide CFC inhalation aerosol 1000 mcg and flunisolide 320 mcg were found to be 2.6 ng/mL and 3.4 ng/mL, respectively. The corresponding mean AUC values for the 12-hr dosing interval were 5.7 ng.hr/mL and 4.7 ng.hr/mL, respectively. At steady state, the mean peak plasma concentrations of 6-OH flunisolide from flunisolide CFC inhalation aerosol 1000 mcg and flunisolide 320 mcg were found to be 0.9 ng/mL and 0.3 ng/mL, respectively. The corresponding mean AUC values for the 12-hr dosing interval were 3.8 ng.hr/mL and 1.1 ng.hr/mL, respectively. The second was a crossover study in 11 subjects after single doses of flunisolide CFC inhalation aerosol 1000 mcg or flunisolide 320 mcg. The mean peak plasma concentrations of flunisolide from the flunisolide CFC inhalation aerosol 1000 mcg and flunisolide 320 mcg were found to be 2.5 ng/mL and 3.3 ng/mL, respectively. The corresponding mean AUC values were 5.1 ng.hr/mL and 5.8 ng.hr/mL, respectively. The mean peak plasma concentrations of 6  -OH flunisolide from flunisolide CFC inhalation aerosol 1000 mcg and flunisolide 320 mcg were found to be 0.8 ng/mL and 0.3 ng/mL, respectively. The corresponding mean AUC values were 3.8 ng.hr/mL and 2.3 ng.hr/mL, respectively.
Controlled clinical studies with flunisolide CFC inhalation aerosol included over 500 treated asthma patients, among them 150 children aged 6 years and older. Open label studies of two years or more duration included more than 120 treated patients. No significant adrenal suppression attributed to flunisolide was seen in these studies.
The potential effects of flunisolide and flunisolide CFC inhalation aerosol on the hypothalamic-pituitary-adrenal (HPA) axis were studied in 2 placebo- and active- controlled studies and 2 active-controlled, open label, long-term studies. In the placebo-controlled studies, the ability to increase cortisol production in response to stress was assessed by the 60 minute cosyntropin (ACTH) stimulation test. For adult and adolescent patients treated with flunisolide 80 mcg, 160 mcg, 320 mcg, or placebo twice daily for 12 weeks, 92% (22/24), 93% (26/28), 93% (26/28), and 92% (22/24) of patients, normal at baseline, respectively, continued to have a normal stimulated cortisol response (peak cortisol 18 mcg/dL and an increase in plasma cortisol 7 mcg/dL within 60 minutes after cosyntropin injection) at trial's end. All patients had peak cortisol levels  18mcg/dL. There was no significant suppression of 24 hour urinary cortisol, and 100% (96/96) of patients treated with flunisolide had normal morning serum cortisol levels at the end of study. For pediatric patients treated with the flunisolide, 80 mcg and 160 mcg or placebo twice daily for 12 weeks, 91% (31/34), 97% (28/29), and 89% (24/27) of patients, respectively, continued to have a normal stimulated cortisol response (as defined above) at trial's end. No suppression of 24-hour urinary cortisol was noted. In these studies, comparable results were obtained in patients treated with flunisolide CFC inhalation aerosol.
In the active-controlled, open label, long-term studies, 99.4% (161/162) of adult and adolescent patients and 98.4% (126/128) pediatric patients treated with flunisolide had normal morning serum cortisol levels ( 5 mcg/dL) after 12 or 52 weeks of treatment, respectively. For patients treated with flunisolide, 92.5% (99/107) continued to have a normal stimulated plasma cortisol response to cosyntropin at trial's end with all having peak cortisol levels  18mcg/dL. In these studies, no suppression of 24-hour urinary cortisol was noted, and comparable results were obtained in patients treated with flunisolide CFC inhalation aerosol.

## Pharmacokinetics
All the data described below is based on studies conducted in subjects 18 to 51 years of age.
Flunisolide is rapidly absorbed after oral inhalation. Mean values for the time to maximum concentration, Tmax, of flunisolide range from 0.09 to 0.17 hr after a single 320 mcg dose of flunisolide. The corresponding mean values for the maximum concentration, Cmax, of flunisolide vary from 1.9 to 3.3 ng/mL. Oral bioavailability is less than 7%. Over the dose range of 80 mcg to 320 mcg of flunisolide, values for Cmax increase proportionately with dose after single as well as multiple dose administration.
Flunisolide is extensively distributed in the body, with mean values for apparent volume of distribution ranging from 170 to 350 L after a single 320 mcg dose of flunisolide.
Flunisolide is rapidly and extensively converted to 6-OH flunisolide and to water-soluble conjugates during the first pass through the liver. Conversion to 6-OH flunisolide, the only circulating metabolite detected in man, is thought to occur via the cytochrome P450 enzyme system, particularly the enzyme CYP3A4. 6-OH flunisolide has a low corticosteroid potency (ten times less potent than cortisol and more than 200 times less potent than flunisolide). Maximum levels of 6-OH flunisolide were 0.66 mcg/mL after a single 320 mcg dose of flunisolide, and 0.71 mcg/mL after multiple doses of flunisolide.
Urinary excretion of flunisolide is low. Less than 1% of the administered dose of flunisolide is recovered in urine after inhalation. The half-life values for 6-OH flunisolide range from 3.1 to 5.1 hrs after administration of flunisolide in the dose range of 160 mcg to 320 mcg.
Twice daily inhalation administration of flunisolide for up to 14 days did not result in appreciable accumulation of flunisolide. Upon multiple dosing with 160 mcg and 320 mcg, the Cmax values were 1.0 ng/mL and 2.1 ng/mL, respectively. The corresponding AUC0-12hr values were 1.2 ng.hr/mL and 2.5 ng.hr/mL.
Flunisolide is rapidly cleared from the body, independent of route of administration or dose administered. Flunisolide is not detectable in plasma twelve hours post-dose. After administration of 320 mcg of flunisolide the elimination half-life ranges from 1.3 to 1.7 hours. After a single 320 mcg dose, mean oral clearance values, not adjusted for bioavailability, range from 83 to 167 L/hr.

## Nonclinical Toxicology
In a 22 month study in Swiss mice, flunisolide at oral doses up to 500 mcg/kg/day (approximately 3 and 4 times the maximum recommended daily inhalation dose  in adults and children on a mg/m2 basis) did not demonstrate any carcinogenic effects.
In a two year study in Sprague Dawley rats, administration of flunisolide in the diet at a dose of 2.5 mcg/kg/day (less than MRDID in adults or children on a mg/m2 basis) resulted in an increased incidence of mammary gland adenomas and islet cell adenomas of the pancreas in females. The significance of these findings for humans is unknown. There were no significant increases in the incidence of any tumor type in female rats at a dose of 1.0 mcg/kg/day (less than MRDID in adults or children on a mg/m2 basis), or in male rats at a dose of 2.5 mcg/kg/day (less than MRDID in adults or children on a mg/m2 basis).
Flunisolide showed no mutagenic activity when tested in in vitro bacterial assay systems (Ames Assay and the Rec-assay) and no clastogenic activity when tested in the in vitro chromosomal aberration assay using Chinese Hamster CHL cells and in the in vivo mouse bone marrow chromosomal aberration assay.

# Clinical Studies
The efficacy of flunisolide has been studied in two double-blind, parallel, placebo-and active-controlled clinical trials of 12 weeks duration involving more than 1250 patients, one in adults and adolescents 12 years of age and older, and one in patients 4-11 years of age. In adults and adolescents, efficacy was evaluated in patients previously treated with inhaled corticosteroids. In children 6 to 11 years of age, efficacy was evaluated in patients previously treated with bronchodilators alone or inhaled corticosteroids. Both trials had a 2- week run-in period followed by a 12-week randomized treatment period. During the run-in period all patients received flunisolide CFC inhalation aerosol 500 mcg twice daily. Patients were then randomized to double-blind treatment with different doses of flunisolide or flunisolide CFC inhalation aerosol and monitored for lung function changes to see if they maintained, improved, or lost stability. Baseline was assessed at the end of the run-in period. The primary endpoint was the change from baseline in percent predicted FEV1 after 12 weeks treatment.
Efficacy was evaluated in 669 asthma patients, 12 to 78 years of age, including 88 patients 12-17 years of age and 581 patients 18 years and older. Mean FEV1 at screening was 2.44 L and mean FEV1 at baseline was 2.72 L following the 2-week run-in period. Patients were randomized to flunisolide 80 mcg, 160 mcg or 320 mcg twice daily, flunisolide CFC inhalation aerosol 250 mcg, 500 mcg, or 1000 mcg twice daily, or placebo. Change from baseline in percent predicted FEV1 over 12 weeks treatment demonstrated that placebo patients deteriorated 4.3% from baseline after 12 weeks of treatment, whereas patients treated with flunisolide 160 mcg or 320 mcg twice daily maintained FEV1 over the course of the study. Results for the comparison to placebo were statistically significant for the 160 and 320 mcg twice daily flunisolide doses (see FIGURE 1), but not for the 80 mcg dose. Secondary endpoints of AM peak expiratory flow rate, AM and PM asthma symptoms, nocturnal awakenings requiring a 2 agonist, and as needed use of inhaled 2 agonists showed differences from baseline favoring flunisolide over placebo. flunisolide and flunisolide CFC inhalation aerosol gave comparable results.
The trial enrolled 583 asthma patients, 4 to 11 years of age, although the primary efficacy parameter was evaluated only in the population of 513 patients 6 to 11 years of age. In these patients, the mean FEV1 at screening was 81.2% predicted, and the mean FEV1 at baseline following a two week run-in period was 87.5% predicted. Patients were randomized to flunisolide 80 mcg or 160 mcg twice daily, flunisolide CFC inhalation aerosol 250 mcg or 500 mcg twice daily, or placebo. Change from baseline in percent predicted FEV1 over 12 weeks in patients 6 years of age and older demonstrated that placebo patients deteriorated 4.0% from baseline after 12 weeks of treatment, whereas patients treated with flunisolide 80 mcg or 160 mcg twice daily maintained FEV1 over the course of the study. Results for the comparison to placebo were statistically significant for the 80 mcg and 160 mcg doses of flunisolide, but there was no added benefit for the 160 mcg BID dose over the 80 mcg BID dose (see FIGURE 2). flunisolide and flunisolide CFC inhalation aerosol gave comparable results in patients 6 years of age and older.

# How Supplied
Flunisolide is an inhalation aerosol in a pressurized metered dose inhaler with a built in spacer that delivers 60 or 120 metered 80 mcg doses

## Storage
Store at 25 C (77 F)

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
Advise patients that localized fungal infections occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, treat with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing with flunisolide therapy, but at times therapy with flunisolide may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised.
Advise patients that flunisolide is not a bronchodilator and is not intended to be used to treat status asthmaticus or to relieve acute asthma symptoms. Treat acute asthma symptoms with an inhaled, short-acting beta-2 agonist such as albuterol. Instruct patients to contact their physicians immediately if there is deterioration of their asthma.
Warn patients who are on immunosuppressant doses of flunisolide to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. Inform patients of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex.
Advise patients that flunisolide may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, instruct patients that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to flunisolide.
Advise patients who are at an increased risk for decreased BMD that the use of corticosteroids may pose an additional risk. Monitor patients and, where appropriate, treat for this condition.
Inform patients that orally inhaled corticosteroids, including flunisolide, may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route.
Long-term use of inhaled corticosteroids, including flunisolide, may increase the risk of some eye problems (cataracts or glaucoma); consider regular eye examinations.
Advise patients to use flunisolide at regular intervals as directed, since its effectiveness depends on regular use. Individual patients will experience a variable time to onset and degree of symptom relief, and the full benefit may not be achieved until treatment has been administered for 2 to 4 weeks. If symptoms do not improve in that time frame or if the condition worsens, patients should not increase dosage, but should contact the physician immediately.
Advise patients not to stop flunisolide or change the dose without talking with a healthcare provider. Advise patients that if they miss a dose to take the next scheduled dose when it is due.
flunisolide contains a built-in spacer. Do not use with any external spacer or holding chamber devices. Instruct patients to prepare the inhaler for use by pulling the built-in purple actuator out from the gray spacer and snapping into an "L" shape prior to use. With use, the appearance of a white ring on the orifice of the actuator and inside the spacer is normal. The performance of flunisolide is not affected by this residue. No cleaning is required.

# Precautions with Alcohol
Alcohol-Flunisolide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Aerobid
- Aerobid-M
- Nasalide
- Nasarel
- Aerospan 

# Look-Alike Drug Names
There is limited information regarding Flunisolide (inhalation) Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price