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Aerospan (Flunisolide Hemihydrate Inhalation) - Warnings and Precautions

 
 



WARNINGS

Particular care is needed in patients who are transferred from systemically active corticosteroids to AEROSPAN Inhalation Aerosol 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its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn.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 AEROSPAN Inhalation Aerosol may provide control of asthmatic symptoms during these episodes, in recommended doses it supplies less than the physiologic amounts of glucocorticoid 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During periods of stress or a severe asthmatic attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume systemic steroids (in large doses) immediately and to contact their physician for further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.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to AEROSPAN Inhalation Aerosol. Lung function (FEV1 or AM PEF), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed 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 AEROSPAN Inhalation Aerosol may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy, e.g. rhinitis, conjunctivitis, eczema, arthritis, and eosinophilic conditions.

Patients who are on 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/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, 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 package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

AEROSPAN Inhalation Aerosol is not a bronchodilator and is not indicated for rapid relief of bronchospasm.

As with other inhaled asthma medications, bronchospasm may occur with an immediate increase in wheezing after dosing. If bronchospasm occurs following dosing with AEROSPAN Inhalation Aerosol, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with AEROSPAN Inhalation Aerosol should be discontinued and alternative therapy instituted.

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 with AEROSPAN Inhalation Aerosol. During such episodes, patients may require therapy with systemic corticosteroids.

PRECAUTIONS

General: During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude and depression, despite maintenance or even improvement of respiratory function. (See DOSAGE AND ADMINISTRATION for details.)

In responsive patients, flunisolide may permit control of asthmatic symptoms 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 AEROSPAN Inhalation Aerosol 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 AEROSPAN Inhalation Aerosol.

Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with AEROSPAN Inhalation Aerosol should be observed 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, reduced bone mineral density, and adrenal suppression may appear in a small number of patients, particularly at higher doses. If such changes occur, the AEROSPAN Inhalation Aerosol dose should be reduced slowly, consistent with accepted procedures for management of asthma symptoms and for tapering of systemic corticosteroids.

The long-term local and systemic effects of AEROSPAN Inhalation Aerosol in human subjects are not fully known. In particular, the effects resulting from chronic use of AEROSPAN Inhalation Aerosol on developmental or immunologic processes in the mouth, pharynx, trachea, and lung are unknown.

Orally inhaled corticosteroids, including flunisolide, may cause a reduction in growth velocity when administered to pediatric patients. A reduction in growth velocity may occur as a result of inadequate control of asthma or from use of corticosteroids for treatment. The potential effects of prolonged treatment on growth velocity should be weighed against clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including AEROSPAN Inhalation Aerosol, each patient should be titrated to his/her lowest effective dose. (See PRECAUTIONS, Pediatric Use.)

Inhaled corticosteroids should be used 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.

Rare instances of glaucoma, increased intraocular pressure, and cataracts have been reported in patients following the long- term administration of inhaled corticosteroids.

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. These infections may require treatment with appropriate antifungal therapy and/or discontinuance of treatment with AEROSPAN Inhalation Aerosol.

Information for Patients:

Patients being treated with AEROSPAN Inhalation Aerosol should receive the following information and instructions. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or beneficial effects. See Patient Information and illustrated Instructions for Using Your AEROSPAN Inhalation Aerosol for supplemental information.

  • Patients should be advised that the effectiveness of AEROSPAN Inhalation Aerosol depends on its regular use and on the proper inhalation-administering technique (see Patient Information and illustrated Instructions for Using Your AEROSPAN Inhalation Aerosol).
  • It is important that patients are instructed to begin inhalation immediately prior to actuation. A delay between actuation and inhalation will lead to inadequate drug delivery from the spacer to the patient. Data show that doses are depleted by 75% or more after waiting one second between actuation and inhalation.
  • Two to 4 weeks may pass before maximum benefit is obtained after starting AEROSPAN Inhalation Aerosol. If symptoms do not improve, or if the condition worsens, patients should not increase dosage, but should contact the physician immediately.
  • Patients should be advised that AEROSPAN Inhalation Aerosol is not a bronchodilator and is not intended for relief of acute asthma symptoms. Patients should be made aware the AEROSPAN Inhalation Aerosol is a controller therapy for asthma, and that it should be taken regularly even if they are asymptomatic.
  • Patients should be instructed to prime the inhaler by releasing two test sprays into the air away from the face before first use of AEROSPAN Inhalation Aerosol, and when the inhaler has not been used for more than 2 weeks.
  • Patients should be instructed that they will receive a new AEROSPAN Inhalation Aerosol unit each time they refill their prescription. Patients should be advised to discard the whole unit including the metal canister, purple actuator, and gray spacer after the labeled number of actuations have been used. The appearance of a white ring on the orifice of the actuator is normal. The performance of AEROSPAN Inhalation Aerosol is not affected by this residue. No cleaning is required. The gray spacer should not be removed from the purple actuator.
  • The gray spacer should not be bitten or chewed.
  • Patients whose systemic corticosteroids have been reduced or withdrawn should be instructed to carry a warning card indicating that they may need supplemental systemic corticosteroids during periods of stress or a severe asthma attack that is not responsive to bronchodilators.
  • Patients who are on immunosuppressant doses of corticosteroids or other immunosuppressant drugs should be warned to avoid exposure to chickenpox or measles. If they are exposed, patients should seek medical advice without delay.
  • Patients should be advised that the use of AEROSPAN Inhalation Aerosol should not be stopped abruptly.
  • Women should consult with their doctor if they are pregnant or intend on becoming pregnant, or if they are breast-feeding a baby.
  • Patients should consult with their doctor if they are allergic to any orally-inhaled corticosteroid.
  • Patients should inform their doctor of other medications they are taking as this medication may not be suitable in some circumstances, and the doctor may wish to use a different medicine.

Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 22 month study in Swiss mice, flunisolide hemihydrate 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 hemihydrate in the diet at a dose of 2.5 mcg/kg/day (less than the maximum recommended daily inhalation dose 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 the maximum recommended daily inhalation dose in adults or children on a mg/m2 basis), or in male rats at a dose of 2.5 mcg/kg/day (less than the maximum recommended daily inhalation dose in adults or children on a mg/m2 basis).

Flunisolide hemihydrate 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.

Studies on the effects of flunisolide hemihydrate on fertility in female rats showed that flunisolide hemihydrate, at an oral dose of 200 mcg/kg/day (approximately 3 times the maximum recommended daily inhalation dose on a mg/m2 basis) impaired fertility, but was devoid of such effects at doses up to 40 mcg/kg/day (less than the maximum recommended daily inhalation dose on a mg/m2 basis).

Pregnancy

Teratogenic Effects: Pregnancy Category C. As with other corticosteroids, flunisolide hemihydrate has been shown to be teratogenic and fetotoxic in rabbits and rats at doses of 40 and 200 mcg/kg/day, respectively, (approximately 1 and 3 times the maximum recommended daily inhalation dose on a mg/m2 basis, respectively). There are no adequate and well-controlled studies of flunisolide hemihydrate in pregnant women. AEROSPAN Inhalation Aerosol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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.

Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.

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 AEROSPAN Inhalation Aerosol is administered to nursing women.

Pediatric Use: The safety and effectiveness of AEROSPAN Inhalation Aerosol has been studied in patients ages 4-17 years of age. The safety and effectiveness of AEROSPAN Inhalation Aerosol has not been studied in patients less than 4 years of age. In clinical studies, the adverse event profile observed in patients exposed to AEROSPAN Inhalation Aerosol 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).

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 AEROSPAN Inhalation Aerosol, 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 AEROSPAN Inhalation Aerosol, each patient should be titrated to the lowest dose that effectively controls his/her symptoms.

Geriatric Use: Clinical studies of AEROSPAN Inhalation Aerosol included 21 patients 65 to 78 years of age exposed to AEROSPAN Inhalation Aerosol. These studies did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. 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.

Page last updated: 2007-05-28

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