AHFS Class:

• Adrenals 68:04

Generic Name(s):

• Flunisolide

Flunisolide is a synthetic fluorinated glucocorticoid.105

Asthma

Flunisolide is used by oral inhalation for the long-term prevention of bronchospasm in patients with asthma.105,107 Orally inhaled flunisolide also may permit a reduction in dosage or discontinuance of systemic corticosteroids in patients who require prolonged administration of oral corticosteroids to control asthma symptoms.105,107

Oral inhalation of flunisolide is contraindicated in the primary treatment of severe acute asthmatic attacks or status asthmaticus when intensive measures (e.g., oxygen, parenteral bronchodilators, IV corticosteroids) are required.105,107,109 Flunisolide oral inhalation is not a bronchodilator, and patients should be warned that the drug should not be used for rapid relief of bronchospasm.105

Mild Persistent Asthma

Drugs for asthma may be categorized as relievers (e.g., bronchodilators taken as needed for acute symptoms) or controllers (principally inhaled corticosteroids or other anti-inflammatory agents taken regularly to achieve long-term control of asthma).107,109 In the stepped-care approach to antiasthmatic drug therapy, current asthma management guidelines and most clinicians recommend initiation of a controller drug such as an anti-inflammatory agent, preferably a low-dose orally inhaled corticosteroid (e.g., 88-264, 88-176, or 176 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler in adolescents and adults, children 5-11 years of age, or children 4 years of age or younger, respectively) as first-line therapy for persistent asthma (i.e., patients with daytime symptoms of asthma more than twice per week, but less than once daily, and nocturnal symptoms of asthma 3-4 times per month), supplemented by as-needed use of a short-acting, inhaled β₂-agonist.104,107,109 For equivalent orally inhaled dosages of corticosteroids, see General Dosage under Dosage and Administration: Dosage, in the Corticosteroids General Statement 68:04.

Moderate Persistent Asthma

According to current asthma management guidelines, therapy with a long-acting β₂-agonist such as salmeterol or formoterol generally is recommended in adults and adolescents who have moderate persistent asthma and daily asthmatic symptoms that are inadequately controlled following addition of low-dose inhaled corticosteroids to as-needed inhaled β₂-agonist treatment.107,109 However, the National Asthma Education and Prevention Program (NAEPP) recommends that the beneficial effects of long-acting inhaled β₂-agonists should be weighed carefully against the increased risk (although uncommon) of severe asthma exacerbations and asthma-related deaths associated with daily use of such agents.107 (See Asthma-related Death and Life-threatening Events, under Cautions: Respiratory Effects, in Salmeterol 12:12.08.12.) Current asthma management guidelines also state that an alternative, but equally preferred option for management of moderate persistent asthma that is not adequately controlled with a low dosage of inhaled corticosteroid is to increase the maintenance dosage to a medium dosage (e.g., exceeding 264 but not more than 440 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler in adults and adolescents).104,107,109

In children 5-11 years of age with moderate persistent asthma that is not controlled with a low dosage of an inhaled corticosteroid, a long-acting inhaled β₂-agonist (e.g., salmeterol, formoterol), a leukotriene modifier (i.e., montelukast, zafirlukast), or extended-release theophylline (with appropriate monitoring) may be added to low-dose inhaled corticosteroid therapy according to current asthma management guidelines; another preferred option is to increase the maintenance dosage of the inhaled corticosteroid to a medium dosage (e.g., exceeding 176 but not more than 352 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler).107 In infants and children 4 years of age or younger with moderate persistent asthma that is not controlled by a low dosage of an inhaled corticosteroid, the only preferred option is to increase the maintenance dosage of the inhaled corticosteroid to a medium dosage (e.g., exceeding 176 but not more than 352 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler).107

Severe Persistent Asthma

Maintenance therapy with an inhaled corticosteroid at medium or high dosages (e.g., exceeding 440 mcg of fluticasone propionate in adults and adolescents or 352 mcg of the drug in children 5-11 years of age [or its equivalent] daily via a metered-dose inhaler) and adjunctive therapy with a long-acting inhaled β₂-agonist is the preferred treatment according to current asthma management guidelines for adults and children 5 years of age or older with severe persistent asthma (i.e., continuous daytime asthma symptoms, nighttime symptoms 7 times per week).104,107,109 In infants and children 4 years of age or younger with severe asthma, maintenance therapy with an inhaled corticosteroid at medium or high dosages (e.g., exceeding 352 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler) and adjunctive therapy with either a long-acting inhaled β₂-agonist or montelukast is recommended in current asthma management guidelines as the only preferred treatment.107

Poorly Controlled Asthma

If asthma symptoms in patients with moderate to severe asthma are very poorly controlled (i.e., at least 2-3 exacerbations per year requiring oral corticosteroids), a short course of an oral corticosteroid (3-10 days) may be added to gain prompt control of asthma.107 Regular use of oral corticosteroids as add-on therapy in adults and children 5 years of age or older with severe asthma who are inadequately controlled with a high-dose inhaled corticosteroid, intermittent oral corticosteroid therapy, and a long-acting inhaled β₂-agonist bronchodilator is suggested, based on consensus and clinical experience.107,109 A short (2-week) course of oral corticosteroids may be considered to confirm clinical response prior to implementing long-term oral corticosteroid therapy.107 Once long-term oral corticosteroid therapy is initiated, the lowest possible effective dosage (i.e., alternate-day or once-daily administration) should be used, and the patient should be monitored carefully for adverse effects.107 Once asthma is well-controlled, repeated attempts should be made to reduce the oral corticosteroid dosage.107 Use of orally inhaled flunisolide as adjunctive therapy in patients who require prolonged administration of systemic corticosteroids to control asthma symptoms may permit a reduction in dosage or discontinuance of systemic corticosteroids.105 When used in recommended dosages in responsive patients, flunisolide oral inhalation may permit control of asthmatic symptoms with less suppression of hypothalamic-pituitary-adrenal (HPA) function compared with therapeutically equivalent oral doses of prednisone.105 For additional details on the stepped-care approach to drug therapy in asthma,103,107,109 see Asthma under Uses: Bronchospasm, in Albuterol 12:12.08.12 and see Asthma under Uses: Respiratory Diseases, in the Corticosteroids General Statement 68:04.

Other Uses

For EENT uses of flunisolide, see 52:08.08.

Administration

Flunisolide is administered by oral inhalation using a metered-dose oral aerosol inhaler with an internal spacer device.105 This oral inhaler should not be used with external spacers or holding chambers.105 Patients should be carefully instructed in the use of the oral inhaler.105 To obtain optimum results, patients should also be given a copy of the patient instructions provided by the manufacturer.105 An adult should carefully supervise a child in the administration of flunisolide for oral inhalation.105 The manufacturer states that the flunisolide oral inhaler should be used by oral inhalation only. 105

The inhaler should be prepared for use by pulling the purple actuator out from the gray spacer and snapping it into place forming an “L” shape.105 The guide lines on the spacer should match up with the lines on the actuator.105 Before the first use, and any time the inhaler has not been used for more than 2 weeks, the inhaler should be primed with 2 test sprays by pressing down on the metal canister 2 times for 1 second each time with the mouthpiece pointed away from the face.105 The inhaler should be held between the thumb and index finger and shaken well immediately prior to use.105

After inhaling then exhaling normally through the mouth, the mouthpiece of the inhaler should be placed into the mouth and the lips closed firmly around it.105 The patient should begin to inhale slowly through the mouth and then press the metal canister down with the index finger for at least 1 second; the patient should continue inhaling through the mouth for 3 more seconds.105 After inhalation is complete, the patient should remove the inhaler from the mouth, close the lips, and hold the breath for at least 10 seconds or as long as comfortable.105 The patient should then exhale and breathe normally.105 If additional inhalations are required, the patient should wait 20 seconds between inhalations, shake the inhaler again, and repeat the procedure.105 Following each treatment, the patient should rinse the mouth thoroughly with water and expectorate to remove drug deposited in the oropharyngeal area.105 The teeth also may be brushed if desired.105

Appearance of a white residue at the opening of the mouthpiece and inside the spacer is normal with use and does not affect the performance of the inhaler.105 Cleaning the oral inhaler is not necessary.105

Dosage

Dosage of flunisolide hemihydrate is expressed in terms of flunisolide.105 Orally inhaled flunisolide with hydrofluoroalkane (HFA: tetrafluoroethane) propellants delivers 80 mcg of flunisolide per metered spray; the commercially available aerosol inhaler delivers 60 metered sprays per 5.1-g canister or 120 metered sprays per 8.9-g canister.105 Dosage must be carefully adjusted according to individual requirements and response.105 After a satisfactory response is obtained, dosage should be decreased gradually to the lowest possible dosage that maintains an adequate clinical response.105 The lowest effective dosage should be achieved, particularly in children, since inhaled corticosteroids have the potential to affect growth.105

The usual initial dosage of flunisolide for adults and adolescents 12 years of age or older given as the inhalation aerosol is 160 mcg (2 sprays) twice daily (320 mcg total daily dosage).105 If required, the dosage may be increased to 320 mcg (4 sprays) twice daily.105 The manufacturer states that a dosage of 320 mcg twice daily (640 mcg total daily dosage) should not be exceeded in adults and adolescents, although higher dosages have been recommended for patients with severe persistent asthma.104,105 Patients should be monitored periodically for effects on the hypothalamic-pituitary-adrenal (HPA) axis.105

In children 6-11 years of age, an initial dosage of 80 mcg (1 spray) twice daily (160 mcg total daily dosage) is recommended.105 If required, the dosage may be increased to 160 mcg (2 sprays) twice daily.105 When the drug is administered on a long-term basis to children, patients should be monitored for effects on growth as well as on the HPA axis.105 The manufacturer states that insufficient information is available to warrant use of the drug in children younger than 6 years of age.105

When orally inhaled flunisolide is administered to patients receiving systemic corticosteroids, the aerosol initially is given concurrently with the maintenance dosage of the systemic corticosteroid.105 After at least 1 week, the systemic corticosteroid is gradually withdrawn.105 (See Dosage and Administration in the Corticosteroids General Statement 68:04.) Gradual withdrawal of systemic corticosteroids following long-term therapy is strongly recommended, since death has occurred in some individuals in whom systemic corticosteroids were withdrawn too rapidly. 105 After systemic corticosteroids have been withdrawn, if exacerbations of asthma occur during flunisolide oral inhalation therapy, short courses of systemic corticosteroids should be given, then tapered as symptoms subside.105

Patients who respond to the drug usually show improvement in pulmonary function within 2-4 weeks of continuous therapy.105

Chemistry and Stability

Chemistry

Flunisolide is a synthetic fluorinated corticosteroid.105

Flunisolide occurs as a hemihydrate, white to creamy white, crystalline powder and is soluble in acetone and ethyl alcohol and practically insoluble in water.105

For oral inhalation, flunisolide is commercially available as an aerosol containing a solution of the drug in a vehicle of ethanol and 1,1,1,2-tetrahydrofluoroethane (HFA 134a) propellant.105

Stability

Because the contents of flunisolide oral inhaler are under pressure, the aerosol container should not be punctured, used or stored near heat or an open flame, exposed to temperatures exceeding 49°C, or placed into a fire or incinerator for disposal.105 Freezing temperatures and prolonged exposure to sunlight also should be avoided.105

Additional Information

For further information on chemistry, pharmacology, pharmacokinetics, cautions, and dosage and administration of flunisolide, see the Corticosteroids General Statement 68:04. For EENT uses, see 52:08.08.

100. National Asthma Education and Prevention Program. Expert panel report II: guidelines for the diagnosis and management of asthma. Bethesda, MD: National Institutes of Health; 1997 Feb.

101. National Asthma Education Program. Executive summary: guidelines for the diagnosis and management of asthma. NIH Publication No. 94-3042A. Washington, DC: US Government Printing Office; 1994 Jul.

102. National Institutes of Health, National Heart, Lung, and Blood Institute. Global initiative for asthma: global strategy for asthma management and prevention NHLBI/WHO Workshop Report. Bethesda, MD: National Institutes of Health. 2007 Dec 19. NIH/NHLBI Publication No. 02-3659. Available from website. Accessed Jul 27, 2008. [Web]

103. British Thoracic Society. Guidelines on the management of asthma. Thorax . 1993; 48(Suppl 2):S1-24.

104. National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma. Update on selected topics-2002. Bethesda, MD: National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program Coordinating Committee; 2003 Jun. Available from National Heart, Lung, and Blood Institute Information Center, NIH Publication No. 02-5074. From website. Accessed 2006 Jan. 5. [Web]

105. Acton Pharmaceuticals, Inc. Aerospan^® (flunisolide) inhalation aerosol prescribing information. Marlborough, MA; 2013 Aug.

106. Acton Pharmaceuticals, Inc, Marlborough, MA: Personal communication.

107. National Asthma Education and Prevention Program. Expert panel report III: guidelines for the diagnosis and management of asthma. 2007 Aug. Bethesda, MD: U.S. Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute. Available from website. Accessed 2013 Sep 19. [Web]

109. National Institutes of Health, National Heart, Lung, and Blood Institute. Global initiative for asthma: global strategy for asthma management and prevention. Bethesda, MD: National Institutes of Health. 2012 Dec. Available from website. Accessed 2013 Sep 19. [Web]