BRONALIDE®
Boehringer Ingelheim
Flunisolide
Corticosteroid Aerosol
Action And Clinical Pharmacology: Flunisolide has demonstrated marked anti-inflammatory and anti-allergic activity in classical test systems. It is a corticosteroid which is several hundred times more potent in animal anti-inflammatory assays than the cortisol standard. When inhaled at therapeutic doses it has potent anti-inflammatory activity locally on the bronchial mucosa.
Following i.v. administration in man of 2 mg flunisolide, plasma concentrations of 12 to 21 ng/mL were observed within 5 minutes. Plasma levels declined with time so that after 6 hours, levels of 1 ng/mL or less were circulating. The plasma half-life was estimated to be 80 to 150 minutes.
Flunisolide 1 mg administered by bronchial inhalation to volunteers produced peak or near peak plasma levels at 2 minutes which remained near this level throughout the first hour before declining at a rate similar to that observed after i.v. administration (plasma half-life of 1.6 to 2 hours). After oral inhalation the peak plasma levels (approximately 1.4 ng/mL) were observed in 1 to 2 hours.
In man, following oral administration of 2 mg flunisolide, peak plasma levels of 20 to 27 ng/mL were obtained in 30 to 60 minutes.
Gargling with an alcoholic mouthwash immediately after oral inhalation did not appreciably affect the systemic availability. Inhalation without using mouthwash resulted in a systemic availability of 39%, compared to 32% in the presence of the mouthwash.
The apparent volume of distribution for flunisolide, estimated after the i.v. administration of a single dose, ranged from approximately 3 L/kg in the rat to 8 L/kg in the mouse. These data indicated that flunisolide was extensively distributed into the body tissues. When 100% plasma was used as the source of protein, about 50% of the added flunisolide (2.5´10 to 50´10 M) was found to be protein-bound.
In man, orally-administered flunisolide was extensively metabolized during its first-pass through the liver; the systemic availability of a 1 mg oral dose was about 20%.
In man, flunisolide was excreted via both the kidney and the liver. The drug was rapidly metabolized with 95% recovered in the first 24 hours (53% in urine; 42% in stool). A major metabolite isolated from the urine of man was 6a, 11b, 16a, 17a, 21-pentahydroxypregna-1, 4-diene-3, 20-dione 16, 17-acetonide (6b -OH metabolite) which had only low corticoid activity and a half-life of 1 to 3 hours. In man, the 6b-OH metabolite accounted for 60 to 75% of the recovered drug in the urine.
The data offer metabolic explanations for the clinical observation that flunisolide can be administered by bronchial inhalation in therapeutically effective doses for extensive periods of time without production of systemic-corticosteroid side effects. After bronchial inhalation, much of the dose is eventually swallowed and metabolized to compounds having weak corticoid activity. The lack of systemic effects could result from the rapid conversion of flunisolide to metabolites having low corticoid activity.
Indications And Clinical Uses: For the control of the signs and symptoms of steroid-responsive bronchial asthma when tolerance to or effectiveness of conventional treatment is unsatisfactory. It is also indicated in steroid dependent asthmatics where a reduction of systemic steroids is desirable.
Contra-Indications: Hypersensitivity to any of the ingredients. Active or quiescent untreated pulmonary tuberculosis, or untreated fungal, bacterial, or viral infections. In status asthmaticus, or in patients with moderate to severe bronchiectasis.
Manufacturers’ Warnings In Clinical States: Patients should be instructed to contact their physician immediately when episodes of asthma which are not responsive to bronchodilators occur during the course of treatment. During such episodes, patients may require therapy with systemic corticosteroids.
Particular care is needed in patients who are transferred from systemic corticosteroids to flunisolide because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic to aerosolized 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 may provide control of asthmatic symptoms during these episodes, it does not provide the systemic steroid which is necessary for coping with these emergencies. During periods of stress or severe asthmatic attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume systemic steroids immediately (in large doses) and to contact their physician for further instruction.
The development of pharyngeal and laryngeal candidiasis is cause for concern because the extent of its penetration of the respiratory tract is unknown. If candidiasis develops, discontinue the treatment and initiate appropriate antifungal therapy. The incidence of candidiasis can generally be held to a minimum by having patients rinse their mouths with water after each inhalation.
During withdrawal from oral corticosteroids, some patients may experience symptoms of steroid withdrawal, e.g. joint and/or muscle pain, lassitude and depression, despite maintenance or even improvement of respiratory function.
Pregnancy and Lactation: Controlled trials relating to fetal risk in humans have not been done. Flunisolide may be secreted in human milk. The use of flunisolide in pregnancy or nursing mothers requires that the possible benefits of the drug be weighed against the potential hazards to the mother, embryo, fetus or nursing infant. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy or those infants nursed by mothers receiving corticosteroids, should be carefully observed for hypoadrenalism.
Children: Insufficient information is available to warrant use in children under the age of 4.
Precautions: The replacement of a systemic steroid with flunisolide has to be gradual and carefully supervised by the physician. The guidelines under Dosage should be followed in all such cases.
Pregnancy: Avoid unnecessary administration of drugs during the first trimester of pregnancy.
It is essential that the patient be instructed that the inhalant is a preventive agent which must be taken at regular intervals and is not to be used during an asthmatic attack.
Transfer of patients from systemic steroid therapy to flunisolide may unmask allergic conditions previously suppressed by the systemic steroid therapy, e.g. rhinitis, conjunctivitis and eczema.
Potential effects on acute, recurrent or chronic infection, including active or quiescent tuberculosis, are not known.
Local effects on developmental or immunologic processes in the mouth, pharynx, trachea, and lung are unknown.
Corticosteroids may mask some signs of infection and new infections may appear. A decreased resistance to localized infection has been observed during corticosteroid therapy.
During long-term therapy, pituitary-adrenal function and hematological status should be periodically assessed.
As with many other pressurized aerosol formulations, flunisolide contains a fluorocarbon propellant. In large doses, these propellants can produce cardiac arrhythmia in animals, as well as sensitize their hearts to adrenaline-induced arrhythmia. Data in humans are meager. Excessive inhalation of the aerosol should, however, be avoided as this carries a potential hazard, both from the propellant as well as from overdosage of the active therapeutic agent contained in the formulation. The recommended dose should not be exceeded and patients should be advised appropriately.
There is an enhanced effect of corticosteroids in patients with hypothyroidism and in those with cirrhosis.
Use ASA cautiously in conjunction with corticosteroids in hypoprothrombinemia.
Advise patients to inform subsequent physicians of the prior use of corticosteroids.
Adverse Reactions: The most frequent adverse reactions in clinical studies were related to the respiratory tract. These were, in decreasing order of frequency: cough, hoarseness, sore throat and wheezing. These occurred in up to 1 in 14 patients. Less frequent reactions were: nausea, infection with candida, glossitis, headache, chest tightness, dry throat, gas, pruritus, loss of smell and taste, abdominal pain, diarrhea, heartburn and rash. These occurred in up to 1 in 50 patients.
Other adverse reactions which occurred less often than 1 in 100 patients were: dyspepsia, sore mouth, rhinitis, throat itch, vomiting, abdominal fullness, acne, capillary fragility, edema, and shortness of breath.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: In case of hypercorticism and/or adrenal suppression, discontinue therapy. tag_DosageDosage
Dosage And Administration: 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 daily for a total daily dose of 2 mg.
Children: Insufficient information is available to warrant use in children under age 4. For children 4 to 15 years of age, 2 inhalations may be administered twice daily for a total dose of 1 mg. Higher doses have not been studied.
There is no evidence that better control of asthma can be achieved by the administration of flunisolide in amounts greater than the recommended doses; higher doses may induce adrenal suppression.
Since the effect of flunisolide depends on its regular use and on the proper technique of inhalation, patients must be instructed to take the inhalations at regular intervals and not as with other aerosols, as they feel necessary. They should also be instructed in the correct method, which is to exhale completely, placing the lips tightly around the mouthpiece and actuate the aerosol early during the next inspiratory period.
In the presence of excessive mucus secretion, the drug may fail to reach the bronchioles. Therefore, if an obvious response is not obtained after 10 days, attempts should be made to remove the mucus with expectorants and/or with a short course of systemic corticosteroid treatment.
Careful attention must be given to patients previously treated for prolonged periods with systemic corticosteroids, when transferred to flunisolide.
Initially, flunisolide and the systemic steroid must be given concomitantly while the dose of the latter is gradually decreased. In adults, the usual rate of withdrawal of the systemic corticoid is the equivalent of 2.5 mg prednisone every 4 days if the patient is under close observation. In children, the rate of withdrawal is 2.5 mg prednisone every 8 days when under close supervision. If continuous supervision is not feasible, the withdrawal of the systemic steroid should be slower, approximately 2.5 mg prednisone (or equivalent) every 10 days in adults and 20 days in children. If withdrawal symptoms appear, the previous dose of the systemic drug should be resumed for a week before further decrease is attempted. Under stressful conditions or when the patient has a severe exacerbation of asthma, after complete withdrawal of the systemic steroid, use of the latter must be resumed in order to avoid relative adrenocortical insufficiency. There are some patients who cannot completely discontinue the oral corticosteroid. In these cases, a minimum maintenance dose should be given in addition to flunisolide.
Availability And Storage: Each canister contains: 100 metered doses of flunisolide aerosol. Nonmedicinal ingredients: propellants (difluorodichloromethane, monofluorotrichloromethane, tetrafluorodichloroethane) and sorbitan trioleate. Each valve depression (actuation) delivers 250 µg of flunisolide.
BRONALIDE® Boehringer Ingelheim Flunisolide Corticosteroid Aerosol
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