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Flunisolide (Oral Inhalation)

Pronunciation

(floo NISS oh lide)

Index Terms

  • AeroBid
  • Flunisolide Hemihydrate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Aerosol Solution, Inhalation:

Aerospan: 80 mcg/actuation (5.1 g [DSC], 8.9 g)

Brand Names: U.S.

  • Aerospan

Pharmacologic Category

  • Corticosteroid, Inhalant (Oral)

Pharmacology

Decreases airway inflammation by suppression of endogenous inflammatory mediators (kinins, histamine, liposomal enzymes, prostaglandins). Inhibits inflammatory cell migration and reverses increased capillary permeability to decrease access of inflammatory cells to the site of inflammation; does not depress hypothalamus.

Absorption

Rapid

Distribution

Extensive; Vd: 170-350 L

Metabolism

Rapid and extensive hepatic metabolism via CYP3A4 to a minimally active metabolite (6 beta-OH flunisolide); also undergoes conjugation

Excretion

Rapid; not detectable in plasma 12-hours post dose; urine (<1% as unchanged drug)

Time to Peak

Within 5-10 minutes

Half-Life Elimination

1.3-1.7 hours

Use: Labeled Indications

Maintenance treatment and prophylactic therapy for asthma; to reduce or eliminate the need for oral corticosteroids in steroid-dependent asthma patients

Guideline recommendations: A low-dose inhaled corticosteroid (in addition to an as-needed short acting beta2-agonist) is the initial preferred long term control medication for children, adolescents, and adult patients with persistent asthma who are candidates for treatment according to a step-wise treatment approach (GINA 2016; NAEPP 2007).

Contraindications

Hypersensitivity to flunisolide or any component of the formulation; acute status asthmaticus or other acute asthma episodes

Dosing: Adult

Asthma: Oral Inhalation: 160 mcg twice daily (morning and evening); maximum dose: 320 mcg twice daily

Asthma Guidelines (NAEPP, 2007) (administer in divided doses twice daily):

“Low” dose: 320 mcg daily

“Medium” dose: >320 to 640 mcg daily

“High” dose: >640 mcg daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Asthma: Oral inhalation:

Children 6 to 11 years: 80 mcg twice daily (morning and evening); maximum dose: 160 mcg twice daily

Children ≥12 years and Adolescents: Refer to adult dosing.

Asthma Guidelines (NAEPP, 2007) (administer in divided doses twice daily):

Children 5 to 11 years:

“Low” dose: 160 mcg daily

“Medium” dose: 320 mcg daily

“High” dose: ≥640 mcg daily

Children ≥12 years and Adolescents: Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment provided in manufacturer’s labeling; however, accumulation not expected to be significant given the rapid and extensive metabolism to less active metabolites and minimal urinary excretion.

Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer’s labeling. Flunisolide is metabolized hepatically; however, systemic absorption may not be clinically significant and accumulation in hepatic impairment is expected to be minimal.

Administration

Shake well before using. Prime inhaler prior to first use and when the inhaler has not been used for >2 weeks by releasing 2 test sprays away from the face. Rinse mouth following use of oral inhalers. Do not immerse the canister into water to determine remaining amount in the canister (ie, “float test”).

Storage

Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Do not puncture; do not use or store near heat or flame. Protect from prolonged sunlight exposure.

Drug Interactions

Aldesleukin: Corticosteroids may diminish the antineoplastic effect of Aldesleukin. Avoid combination

Amphotericin B: Corticosteroids (Orally Inhaled) may enhance the hypokalemic effect of Amphotericin B. Monitor therapy

Ceritinib: Corticosteroids may enhance the hyperglycemic effect of Ceritinib. Monitor therapy

Corticorelin: Corticosteroids may diminish the therapeutic effect of Corticorelin. Specifically, the plasma ACTH response to corticorelin may be blunted by recent or current corticosteroid therapy. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Corticosteroids (Orally Inhaled). Management: Orally inhaled fluticasone propionate with a strong CYP3A4 inhibitor is not recommended. Monitor therapy

Deferasirox: Corticosteroids may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

Desmopressin: Corticosteroids (Orally Inhaled) may enhance the hyponatremic effect of Desmopressin. Avoid combination

Hyaluronidase: Corticosteroids may diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving corticosteroids (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Consider therapy modification

Loop Diuretics: Corticosteroids (Orally Inhaled) may enhance the hypokalemic effect of Loop Diuretics. Monitor therapy

Loxapine: Agents to Treat Airway Disease may enhance the adverse/toxic effect of Loxapine. More specifically, the use of Agents to Treat Airway Disease is likely a marker of patients who are likely at a greater risk for experiencing significant bronchospasm from use of inhaled loxapine. Management: This is specific to the Adasuve brand of loxapine, which is an inhaled formulation. This does not apply to non-inhaled formulations of loxapine. Avoid combination

Thiazide and Thiazide-Like Diuretics: Corticosteroids (Orally Inhaled) may enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Adverse Reactions

Frequency not always defined.

>10%:

Central nervous system: Headache (9% to 14%)

Respiratory: Pharyngitis (17% to 18%), rhinitis (4% to 16%)

1% to 10%:

Cardiovascular: Chest pain (1% to 3%), edema (1% to 3%), capillary fragility (≥1%), chest tightness (≥1%), hypertension (≥1%), palpitations (≥1%), peripheral edema (≥1%), tachycardia (≥1%)

Central nervous system: Pain (2% to 5%), dizziness (1% to 3%), insomnia (1% to 3%), migraine (1% to 3%), voice disorder (1% to 3%), anosmia (≥1%), anxiety (≥1%), depression (≥1%), fatigue (≥1%), hyperactivity (≥1%), hypoactivity (≥1%), irritability (≥1%), malaise (≥1%), mood changes (≥1%), numbness (≥1%), shakiness (≥1%), vertigo (≥1%)

Dermatologic: Skin rash (2% to 4%), erythema multiforme (1% to 3%), acne vulgaris (≥1%), diaphoresis (≥1%), eczema (≥1%), pruritus (≥1%), urticaria (≥1%)

Endocrine & metabolic: Weight gain (≥1%), adrenal suppression, adrenocortical insufficiency, growth suppression (children and adolescents), hypercorticoidism

Gastrointestinal: Vomiting (≤5%), dyspepsia (2% to 4%), abdominal pain (1% to 3%), diarrhea (1% to 3%), dysgeusia (1% to 3%), gastroenteritis (1% to 3%), nausea (1% to 3%), oral candidiasis (1% to 3%), ageusia (≥1%), constipation (≥1%), decreased appetite (≥1%), epigastric fullness (≥1%), flatulence (≥1%), glossitis (≥1%), heartburn (≥1%), mouth irritation (≥1%), sore throat (≥1%), stomach discomfort (≥1%), oropharyngeal candidiasis

Genitourinary: Urinary tract infection (1% to 4%), dysmenorrhea (1% to 3%), vaginitis (1% to 3%)

Hematologic & oncologic: Lymphadenopathy (≥1%)

Hypersensitivity: Hypersensitivity reaction (4% to 5%)

Infection: Bacterial infection (4%), infection (1% to 3%), cold symptoms (≥1%), influenza (≥1%)

Neuromuscular & skeletal: Back pain (1% to 3%), myalgia (1% to 3%), neck pain (1% to 3%), weakness (≥1%), decreased bone mineral density

Ophthalmic: Conjunctivitis (1% to 3%), blurred vision (≥1%), eye discomfort (≥1%), eye infection (≥1%), cataract, glaucoma, increased intraocular pressure

Otic: Otalgia (1% to 3%), otitis (≥1%)

Respiratory: Cough (9%), sinusitis (7% to 9%), epistaxis (3%), bronchitis (1% to 3%), laryngitis (1% to 3%), bronchospasm (≥1%), chest congestion (≥1%), dry throat (≥1%), dyspnea (≥1%), hoarseness (≥1%), increased bronchial secretions (≥1%), nasal congestion (≥1%), nasal mucosa irritation (≥1%), pleurisy (≥1%), pneumonia (≥1%), rhinorrhea (≥1%), sinus congestion (≥1%), sinus discomfort (≥1%), sinus drainage (≥1%), sinus infection (≥1%), sneezing (≥1%), throat irritation (≥1%), upper respiratory tract infection (≥1%), wheezing (≥1%), exacerbation of asthma

Miscellaneous: Fever (1% to 7%)

Warnings/Precautions

Concerns related to adverse effects:

• Adrenal suppression: May cause hypercorticism or suppression of hypothalamic-pituitary-adrenal (HPA) axis, particularly in younger children, in patients receiving high doses for prolonged periods, or when used with inhaled or systemic corticosteroids (even alternate-day dosing). HPA axis suppression may lead to adrenal crisis. Withdrawal and discontinuation of a corticosteroid should be done slowly, carefully, and may require several months. Particular care is required when patients are transferred from systemic corticosteroids to inhaled products due to possible adrenal insufficiency or withdrawal from steroids, including an increase in allergic symptoms. Patients receiving >20 mg per day of prednisone (or equivalent) may be most susceptible. Fatalities have occurred due to adrenal insufficiency in asthmatic patients during and after transfer from systemic corticosteroids to aerosol steroids; aerosol steroids do not provide the systemic effects needed to treat patients having trauma, surgery, or infections. Select surgical patients on long-term, high-dose, inhaled corticosteroid (ICS), should be given stress doses of hydrocortisone intravenously during the surgical period and the dose reduced rapidly within 24 hours after surgery (NAEPP, 2007). Do not use flunisolide to transfer patients from oral corticosteroid therapy.

• Bronchospasm: May occur with wheezing after inhalation; if this occurs, treat with a fast-acting bronchodilator. Stop flunisolide therapy and select an alternative agent.

• Immunosuppression: Prolonged use of corticosteroids may also increase the incidence of secondary infection, mask acute infection (including fungal infections), prolong or exacerbate viral infections, or limit response to vaccines. Exposure to chickenpox and measles should be avoided; use with caution in patients with ocular herpes simplex. Close observation is required in patients with latent tuberculosis and/or TB reactivity; restrict use in active TB (only in conjunction with antituberculosis treatment).

• Kaposi's sarcoma: Prolonged treatment with corticosteroids has been associated with the development of Kaposi's sarcoma (case reports); if noted, discontinuation of therapy should be considered.

• Psychiatric disturbances: Corticosteroid use may cause psychiatric disturbances, including depression, euphoria, insomnia, mood swings, and personality changes. Pre-existing psychiatric conditions may be exacerbated by corticosteroid use.

Disease-related concerns:

• Asthma: Supplemental steroids (oral or parenteral) may be needed during stress or severe asthma attacks. Not to be used in status asthmaticus or for the relief of acute bronchospasm.

• Cardiovascular disease: Use with caution in patients with HF; long-term use has been associated with fluid retention and hypertension.

• Diabetes: Use with caution in patients with diabetes mellitus; may alter glucose production/regulation leading to hyperglycemia.

• Gastrointestinal disease: Use with caution in patients with GI diseases (diverticulitis, peptic ulcer, ulcerative colitis) due to perforation risk.

• Hepatic impairment: Use with caution in patients with hepatic impairment, including cirrhosis; long-term use has been associated with fluid retention.

• Myasthenia gravis: Use with caution in patients with myasthenia gravis; exacerbation of symptoms has occurred especially during initial treatment with corticosteroids.

• Myocardial infarct (MI): Use with caution following acute MI; corticosteroids have been associated with myocardial rupture.

• Ocular disease: Use with caution in patients with cataracts and/or glaucoma; increased intraocular pressure, open-angle glaucoma, and cataracts have occurred with prolonged use. Consider routine eye exams in chronic users.

• Osteoporosis: Use with caution in patients with osteoporosis; high doses and/or long-term use of corticosteroids have been associated with increased bone loss and osteoporotic fractures.

• Renal impairment: Use with caution in patients with renal impairment; fluid retention may occur.

• Seizure disorders: Use with caution in patients with a history of seizure disorder; seizures have been reported with adrenal crisis.

• Thyroid disease: Changes in thyroid status may necessitate dosage adjustments; metabolic clearance of corticosteroids increases in hyperthyroid patients and decreases in hypothyroid ones.

Special populations:

• Pediatric: Orally-inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients (~1 centimeter per year [range 0.3-1.8 cm per year] and related to dose and duration of exposure). To minimize the systemic effects of orally-inhaled corticosteroids, each patient should be titrated to the lowest effective dose. Growth should be routinely monitored in pediatric patients.

Other warnings/precautions:

• Discontinuation of therapy: Withdraw systemic therapy with gradual tapering of dose. There have been reports of systemic corticosteroid withdrawal symptoms (eg, joint/muscle pain, lassitude, depression) when withdrawing oral inhalation therapy.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Hypoadrenalism may occur in infants born to mothers receiving corticosteroids during pregnancy. Based on available data, an overall increased risk of congenital malformations or a decrease in fetal growth has not been associated with maternal use of inhaled corticosteroids during pregnancy (Bakhireva, 2005; NAEPP, 2005; Namazy, 2004). Uncontrolled asthma is associated with adverse events in pregnancy (increased risk of perinatal mortality, pre-eclampsia, preterm birth, low birth weight infants). Inhaled corticosteroids are recommended for the treatment of asthma during pregnancy (most information available using budesonide) (ACOG, 2008; NAEPP, 2005).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience rhinitis, throat irritation, or rhinorrhea. Have patient report immediately to prescriber signs of infection, fatigue, irritability, tremors, tachycardia, confusion, sweating, dizziness, redness or white patches in mouth or throat, difficulty breathing, wheezing, cough, shortness of breath, excessive weight gain, swelling of arms or legs, severe headache, arrhythmia, angina, menstrual irregularities, bone pain, joint pain, severe loss of strength and energy, vision changes, mood changes, behavioral changes, or depression (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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