INFORMATION FOR HEALTH PROFESSIONALS
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Bronconex Acticap Dry Powder Inhaler contains either 200mcg or 400mcg of mometasone furoate anhydrous and lactose. The powder inhaler assembly is white with a maroon base. The cap contains a desiccant cartridge.
Mometasone furoate is a topical glucocorticosteroid with local anti-inflammatory properties .
It is likely that much of the mechanism for the anti-allergic and anti-inflammatory effects of mometasone furoate lies in its ability to inhibit the release of mediators of the inflammatory cascade. Mometasone furoate significantly inhibits the release of leukotrienes from leukocytes of allergic patients. In cell culture, mometasone furoate demonstrated high potency in inhibition of synthesis and release of IL-1, IL-5, IL-6 and TNF-α it is also a potent inhibitor of the production of the Th2 cytokines, IL-4 and IL-5, from human CD4+T-cells.
Mometasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor, which is approximately 12 times that of dexamethasone, 7 times that of triamcinolone acetonide, 5 times that of budesonide and 1.5 times that of fluticasone.
Double-blind placebo-controlled trials of 12-week duration have shown that treatment with Bronconex Acticap at delivered doses within the range of 200-800 mcg per day resulted in improved lung function as measured by FEV1 and peak expiratory flow, improved asthma symptom control and decreased need for inhaled beta-2 agonist. Improved lung function was observed within 24 hours of the start of treatment in some patients, although maximum benefit was not achieved before 1 to 2 weeks or longer. Improved lung function was maintained for the duration of treatment.
In asthmatic patients, repeated administration of Bronconex Acticap for 4 weeks at doses of 200mcg twice daily to 1200mcg once daily showed no evidence of clinically relevant HPA-axis suppression at any dose level and was associated with detectable systemic activity only at a dose of 1600 mcg per day. In long-term clinical trials using doses up to 800mcg per day, there was no evidence of HPA axis suppression, as assessed by reductions in morning plasma cortisol levels or abnormal responses to cosyntropin.
Clinical trials in healthy volunteers demonstrated a low rate of systemic bioavailability and essentially complete first pass metabolism by the liver following oral inhalation of mometasone furoate.
After oral inhalation of Bronconex Acticap at the recommended doses of 200mcg to 400mcg per day, plasma concentration-time data for mometasone furoate were highly variable, with mean values generally near or below the limit of quantitation (LOQ) of the analytic assay. After oral inhalation, neither half-life nor volume of distribution (Vdarea) could be determined. After intravenous bolus administration, the mean half-life was 4.5 hours and the Vdarea was 332 L.
Bronconex Acticap is indicated for prophylactic therapy in the management of patients with asthma of all severities, including patients who have been dependent upon either inhaled or systemically administered corticosteroids and non-corticosteroid-dependent patients inadequately controlled on other drug regimens.
Bronconex Acticap is recommended for use in adults and adolescents 12 years of age and older.
The recommended starting dose of Bronconex therapy for most patients, whether previously maintained on either bronchodilators alone or inhaled corticosteroids, is 400mcg once daily. Some patients may be more adequately controlled on 400mcg given in two divided doses (200mcg twice daily). Dose reduction to 200mcg once daily may be an effective maintenance dose for some patients.
For patients with severe asthma who may require oral corticosteroids, the recommended starting dose of Bronconex Acticap is 400mcg twice daily, which is the maximum recommended dose. Once reduction of oral steroid dose is complete (see below), titrate Bronconex Acticap to the lowest effective dose.
Bronconex Acticap demonstrated improved lung function within 24 hours after the first dose. In some patients, however, maximum benefit may not be achieved before 1 to 2 weeks or longer.
Safety and effectiveness in children less than 12 years of age have not been established.
Adverse events in the elderly population (≥ 65 years) were similar in type and incidence to those reported in younger patients.
The patient needs to be instructed on how to use the inhaler correctly.
Prior to removing the cap, be sure the dose counter and the pointer on the cap are aligned. The inhaler can be opened by removing the white cap while holding the maroon-coloured base down, gripping the base and twisting the cap counter-clockwise. The counter will register the number down by one count. Instruct the patient to place the inhaler in the mouth, closing the lips around the mouthpiece and to breathe in rapidly and deeply. Then, the inhaler is removed from the mouth and the breath held for about 10 seconds, or as long as comfortable. The patient is not to breathe out through the inhaler. To close, replace the cap immediately after each inhalation, loading for next dose by rotating the cap clockwise while gently pressing down until a click sound is heard and the cap is fully closed. The arrow on the cap will be fully aligned with the counter window. Rinsing the mouth after inhalation is advised.
The digital dose counter display will indicate when the last dose has been delivered. After dose 01, the counter will read 00 and the cap will lock, at which time the unit must be discarded. The inhaler must be kept clean and dry at all times. The outside of the mouthpiece can be cleaned with a dry cloth or tissue; not water. (see Package Leaflet for detailed instructions).
Initially, in patients with severe asthma, Bronconex Acticap is for use concurrently with the patient's usual maintenance dose of systemic corticosteroid. After approximately one week, gradual withdrawal of the systemic corticosteroid is initiated by reducing the daily or alternate daily dose.
The next reduction is made after an interval of one to two weeks, depending on the response of the patient. Generally, these decrements are not to exceed 2.5mg of prednisone daily or its equivalent. A slow rate of withdrawal is strongly recommended. During withdrawal of oral corticosteroids, patients must be carefully monitored for signs of unstable asthma, including objective measures of airway function, and for adrenal insufficiency (see PRECAUTIONS).
During dose reduction, some patients may experience systemic corticosteroid withdrawal, e.g. joint and/or muscular pain, lassitude and depression, despite maintenance or even improvement in pulmonary function. Such patients are to be encouraged to continue with Bronconex Acticap treatment, but must be monitored for objective signs of adrenal insufficiency. If evidence of adrenal insufficiency occurs, increase the systemic corticosteroid doses temporarily and thereafter continue withdrawal more slowly. During periods of stress or severe asthma attack, these patients may require supplementary treatment with systemic corticosteroids.
Patients with known hypersensitivity to mometasone furoate or lactose.
During clinical trials, oral candidiasis, which is associated with the use of this class of drugs, occurred in some patients. This infection may require treatment with appropriate antifungal therapy or discontinuance of Bronconex Acticap (see ADVERSE EFFECTS).
As with other inhaled asthma medications, bronchospasm may occur with an immediate increase in wheezing after dosing. If bronchospasm occurs following dosing with the Bronconex Acticap, immediate treatment with a fast-acting inhaled bronchodilator is recommended. Treatment with the Bronconex Acticap should be discontinued and alternative therapy instituted.
Particular care is needed for patients who are transferred from systemically active corticosteroids to the Bronconex Acticap, 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 hypopituitary-adrenal (HPA) axis function.
During periods of stress, including trauma, surgery, infection or a severe asthma attack, patients transferred from systemic corticosteroids will require supplementary treatment with a short course of systemic corticosteroids, which is gradually tapered as symptoms subside. It is recommended that such patients carry a supply of oral corticosteroids and a warning card indicating their need and recommended dosage of systemic corticosteroids during stressful periods. Periodic testing of adrenocortical function, particularly measurement of early morning plasma cortisol levels, is recommended.
Transfer of patients from systemic corticosteroid therapy to Bronconex Acticap may unmask pre-existing allergic conditions previously suppressed by systemic corticosteroid therapy.
Bronconex Acticap is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm.
Instruct patients to contact their physician immediately when asthmatic episodes are not responsive to bronchodilators during treatment with Bronconex Acticap. During such episodes, patients may require systemic corticosteroid therapy.
Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma.
Bronconex Acticap will often permit control of asthma symptoms with less suppression of HPA axis function than therapeutically equivalent oral doses of prednisone. Although mometasone furoate has demonstrated low systemic bioavailability at the recommended dosage, it is absorbed into the circulation and can be systemically active at higher doses. Thus, to maintain its profile of limited potential for HPA axis suppression, recommended doses of Bronconex Acticap must not be exceeded, and must be titrated to the lowest effective dose for each individual patient. When prescribing Bronconex Acticap, physicians are advised to consider that sensitivity to cortisol production may vary from patient to patient.
There is no evidence that the use of Bronconex Acticap in amounts greater than recommended will increase efficacy.
Use Bronconex Acticap with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract, or in untreated fungal, bacterial, systemic viral infections or ocular herpes simplex.
Advise patients who are receiving corticosteroids or other immunosuppressant medicines of the risk of exposure to certain infections (eg chickenpox, measles) and of the importance of obtaining medical advice if such exposure occurs. This is of particular importance in children.
When using inhaled corticosteroids, the possibility for clinically significant adrenal suppression may occur, especially after treatment with higher than recommended doses. This must be considered during periods of stress or elective surgery, when additional systemic corticosteroids may be needed. However, during clinical trials there was no evidence of HPA axis suppression after prolonged treatment with Bronconex Acticap at doses ≤ 800mcg per day.
There are no adequate and well-controlled studies in pregnant women. However, plasma concentrations of mometasone furoate are generally very low following inhaled administration; thus, fetal exposure is expected to be negligible and the potential for reproductive toxicity low.
As with other inhaled corticosteroid preparations, Bronconex Acticap must not be used during pregnancy unless the potential benefit justifies the potential risk to the mother or fetus. Infants born of mothers who received corticosteroids during pregnancy must be observed carefully for hypoadrenalism.
As with other inhaled corticosteroid preparations, women who are breastfeeding must not use Bronconex Acticap unless the potential benefit justifies any potential risk to the infants.
Mometasone furoate is not considered to be genotoxic. There was no evidence of mutagenicity in in vitro tests which included tests for reverse mutation in Salmonella typhimurium and Escherichia coli and forward gene mutation in a mouse lymphoma cell line. Limited evidence of clastogenicity was obtained in Chinese Hamster ovary cells, although this finding was not confirmed in a second assay in Chinese Hamster lung cells in vitro, nor in vivo assays including a chromosomal aberration assay in mouse spermatogonia, a mouse micronucleus assay or in a rat bone marrow clastogenicity assay. Mometasone furoate did not cause DNA damage in rat liver cells.
As with other corticosteroids, at exposure levels associated with marked signs of systemic corticosteroid toxicity, mometasone furoate had progestogenic effects on the female reproductive tract and mammary glands in animal models. However, fertility was unimpaired in a reproductive toxicity study carried out in rats.
The most common undesirable effects reported in placebo-controlled clinical studies were oral candidiasis, pharyngitis and headache. Oral candidiasis occurred in 6% of patients treated with Bronconex Acticap 200mcg twice daily and 2% and 4% of patients treated with 200mcg and 400mcg once daily respectively. The incidence in placebo-treated patients was 1%.
In comparison, among patients with severe asthma treated with oral corticosteroids who received Bronconex Acticap 400mcg twice daily for 12 weeks, oral candidiasis was reported by 20% of patients (vs. 9% with placebo), and dysphonia by 7% of patients (vs. 0% with placebo). These effects were considered treatment-related.
Treatment-related pharyngitis was reported by 4% of patients treated with Bronconex Acticap 200mcg twice daily. In patients treated once daily, the incidence was 3% to 7% at the 200mcg dose and 3% at the 400mcg dose, vs placebo-treated patients, 4%.
Related headache was reported by 3% to 7% of patients in active treatment groups and in 5% of placebo-treated patients.
There was no suggestion of an increased risk for undesirable effects in adolescents or patients 65 years of age or older.
Systemic effects of inhaled corticosteroids may occur, particularly when prescribed at high doses for prolonged periods. No systemic undesirable effects were reported in clinical trials with Bronconex Acticap.
Rare cases of glaucoma, increased intraocular pressure and cataracts have been reported with the use of inhaled corticosteroids.
Co-administration of Bronconex Acticap with the potent CYP3A4 enzyme inhibitor ketoconazole causes small but marginally significant (p=0.09) decreases in serum cortisol AUC(0-24) . However, these changes are unlikely to be of clinical significance.
Because of the low systemic bioavailability of Bronconex Acticap, overdose is unlikely to require any therapy other than observation, followed by initiation of the appropriate prescribed dosage. Inhalation or oral administration of excessive doses of corticosteroids may lead to suppression of HPA axis function.
18 months when stored below 25°C.
Store in original foil package until opened. After opening the package, keep the inhaler in a dry place at a temperature below 25°C. Clean the outside of the mouthpiece with a dry cloth or tissue; avoid contact with water.
Prescription-only medicine
Dry powder inhaler, 200mcg/dose and 400mcg/dose: 30 or 60 doses.
Nil
Schering-Plough Pty Limited
33 Whakatiki Street
Upper Hutt
Wellington NEW ZEALAND
Tel: (04) 528 1900
7 September 2001