Date of Revision: August 08, 2008

Control Number: 121853

(c)

GlaxoSmithKline Inc. 2008. All rights reserved.

(r)

FLOVENT, DISKUS and BABYHALER are registered trademarks, used under license by GlaxoSmithKline Inc.

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 9 DRUG INTERACTIONS 12 DOSAGE AND ADMINISTRATION 13 OVERDOSAGE 17 ACTION AND CLINICAL PHARMACOLOGY 18 STORAGE AND STABILITY 19 SPECIAL HANDLING INSTRUCTIONS 19 DOSAGE FORMS, COMPOSITION AND PACKAGING 19

PART II: SCIENTIFIC INFORMATION 20

PHARMACEUTICAL INFORMATION 20 CLINICAL TRIALS 21 DETAILED PHARMACOLOGY 24 TOXICOLOGY 27 REFERENCES 32

PART III: CONSUMER INFORMATION. 35

PART III: CONSUMER INFORMATION. 40

PrFLOVENT(r) HFA fluticasone propionate inhalation aerosol

PrFLOVENT(r) DISKUS(r) fluticasone propionate powder for inhalation

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

For a complete listing see Dosage Forms, Composition and Packaging section.

CONTRAINDICATIONS

Patients with a history of hypersensitivity to any of its ingredients (see the Dosage Forms, Composition and Packaging section) and in patients with untreated fungal, bacterial or tuberculous infections of the respiratory tract. Patients with IgE mediated allergic reactions to lactose or milk (see the Dosage Forms, Composition and Packaging section). In the primary treatment of status asthmaticus or other acute episodes of asthma, or in patients with moderate to severe bronchiectasis.

WARNINGS AND PRECAUTIONS

General

It is essential that the patients be instructed that FLOVENT(r) (fluticasone propionate) is a preventative agent which must be taken daily at the intervals recommended by their doctors and is not to be used as acute treatment for an asthmatic attack. Patients should be advised to inform subsequent physicians of the prior use of corticosteroids. As with all non-CFC metered-dose inhalers, it is important that asthma control and adverse reactions be reassessed by the physician when switching from an inhaler formulated with CFC propellant to one with non-CFC propellant.

Discontinuance

Treatment with FLOVENT(r) should not be stopped abruptly, but tapered off gradually.

Ear/Nose/Throat

See Immune, Candidiasis.

Endocrine and Metabolism

Systemic Steroid Replacement by Inhaled Steroid

Particular care is needed in asthmatic patients who are transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred during and after transfer. For the transfer of patients being treated with oral corticosteroids, FLOVENT(r) should first be added to the existing oral steroid therapy, which is then gradually withdrawn Patients with adrenocortical suppression should be monitored regularly and the oral steroid reduced cautiously. Some patients transferred from other inhaled steroids or oral steroids remain at risk of impaired adrenal reserve for a considerable time after transferring to inhaled fluticasone propionate. 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 FLOVENT(r) may provide control of asthmatic symptoms during these episodes, it does not provide the systemic steroid which is necessary for coping with these emergencies. The physician may consider supplying oral steroids for use in times of stress (e.g. worsening asthma attacks, chest infections, surgery) (see Overdosage section). During periods of stress or a severe asthmatic attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume systemic steroids 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. To assess the risk of adrenal insufficiency in emergency situations, routine tests of adrenal cortical function, including measurement of early morning and evening cortisol levels, should be performed periodically in all patients. An early morning resting cortisol level may be accepted as normal only if it falls at or near the normal mean level. Transfer of patients from systemic steroid therapy to FLOVENT(r) may unmask allergic conditions outside the pulmonary tract that were previously suppressed by the systemic steroid therapy (e.g. rhinitis, conjunctivitis and eczema). These allergies should be symptomatically treated with anti-histamine and/or topical preparations, including topical steroids. The replacement of a systemic steroid with inhaled steroid must be gradual and carefully supervised by the physician since upon withdrawal, systemic symptoms (e.g. joint and/or muscular pain, lassitude, and depression) may occur despite maintenance or improvement of respiratory function. The guidelines under Dosage and Administration should be followed in all such cases.

Systemic Effects

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 (see Overdosage section). Possible systemic effects include Cushing's Syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. It is important, therefore, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control is maintained (see Adverse Reactions section). The long-term effects of fluticasone propionate in human subjects are still unknown. The local effects of the drug on developmental or immunologic processes in the mouth, pharynx, trachea, and lungs are unknown. There is also no information about the possible long-term systemic effects of the agent (see Monitoring and Laboratory Tests). During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving intranasal or inhaled fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see Drug Interactions section).

Metabolic Effects

Certain individuals can show greater susceptibility to the effects of inhaled corticosteroid than do most patients. There is an enhanced effect of corticosteroids on patients with hypothyroidism. There have been very rare reports of increases in blood glucose levels (see ADVERSE REACTIONS) and this should be considered when prescribing to patients with a history of diabetes mellitus.

Hematologic

Eosinophilic Conditions

In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions, with some patients presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate. Cases of serious eosinophilic conditions have also been reported with other inhaled corticosteroids in this clinical setting. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between fluticasone propionate and these underlying conditions has not been established.

Hepatic/Biliary/Pancreatic

There is an enhanced effect of corticosteroids on patients with cirrhosis.

Immune

Candidiasis

Therapeutic dosages frequently cause the appearance of Candida albicans (thrush) in the mouth and throat. The development of pharyngeal and laryngeal candidiasis is a cause for concern because the extent of its penetration into the respiratory tract is unknown. Patients may find it helpful to rinse and gargle with water after using fluticasone propionate. Symptomatic candidiasis can be treated with topical anti-fungal therapy while still continuing to use FLOVENT(r).

Infection

Corticosteroids may mask some signs of infections and new infections may appear. 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 susceptible children or adults on corticosteroids. In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect 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 intramuscular pooled immunoglobulin (IG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered.

Respiratory

As with other inhalation therapy, paradoxical bronchospasm may occur characterized by an immediate increase in wheezing after dosing. This should be treated immediately with a fast-acting inhaled bronchodilator (e.g. salbutamol) to relieve acute asthmatic symptoms. FLOVENT(r) should be discontinued immediately, the patient assessed, and if necessary, alternative therapy instituted.

Special Populations

Use In Women

Pregnant Women

The safety of fluticasone propionate in pregnancy has not been established. If used, the expected benefits should be weighed against the potential risk to the fetus, particularly during the first trimester of pregnancy. Like other glucocorticoids, fluticasone propionate is teratogenic to rodent species (see Toxicology section). Adverse effects typical of potent corticosteroids are only seen at high systemic exposure levels; administration by inhalation ensures minimal systemic exposure. The relevance of these findings to humans has not yet been established since well-controlled trials relating to foetal risk in humans are not available. Infants born of mothers who have received substantial doses of glucocorticoids during pregnancy should be carefully observed for hypoadrenalism.

Nursing Women

Glucocorticoids are excreted in human milk. The excretion of fluticasone propionate into human breast milk has not been investigated. When measurable plasma levels were obtained in lactating laboratory rats following subcutaneous administration there was evidence of fluticasone propionate in the breast milk. However, plasma levels in patients following inhaled fluticasone propionate at recommended doses are likely to be low. The use of fluticasone propionate in nursing mothers requires that the possible benefits of the drug be weighted against the potential risk to the infant.

Pediatrics (12 months of age and older)

Fluticasone propionate is not presently recommended for children younger than 12 months of age due to limited clinical data in this age group. See also Monitoring and Laboratory Tests.

Monitoring and Laboratory Tests

Increasing use of fast-acting inhaled bronchodilators to control symptoms indicates deterioration of asthma control. Sudden and progressive deterioration in asthma control is potentially life-threatening and consideration should be given to increasing corticosteroid dosage. Patients should be instructed to contact their physicians if they find that relief with short-acting bronchodilator treatment becomes less effective or they need more inhalations than usual. During such episodes, patients may require therapy with systemic corticosteroids. FLOVENT(r) is not indicated for rapid relief of bronchospasm but for regular daily treatment of the underlying inflammation. Patients will require a fast and short acting inhaled bronchodilator (e.g. salbutamol) to relieve acute asthmatic symptoms. There is no evidence that control of bronchial asthma can be achieved by the administration of FLOVENT(r) in amounts greater than the recommended dosages. Lack of response or severe exacerbations of asthma should be treated by increasing the dose of FLOVENT(r) and, if necessary, by giving a systemic steroid and/or an antibiotic if there is an infection. During long-term therapy, HPA axis function and haematological status should be assessed periodically. It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored (see Adverse Reactions section).

DRUG INTERACTIONS

Overview

Under normal circumstances, low plasma concentrations of fluticasone propionate are achieved after inhaled dosing, due to extensive first pass metabolism and high systemic clearance mediated by cytochrome P450 3A4 in the gut and liver. Hence, clinically significant drug interactions involving fluticasone propionate are unlikely. A drug interaction study of intranasal fluticasone propionate in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can greatly increase fluticasone propionate plasma concentrations, resulting in markedly reduced serum cortisol concentrations. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving intranasal or inhaled fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. This study has shown that other inhibitors of cytochrome P450 3A4 produce negligible (erythromycin) and minor (ketoconazole) increases in systemic exposure to fluticasone propionate without notable reductions in serum cortisol concentrations. However, there have been a few case reports during worldwide post-market use of adrenal cortisol suppression associated with concomitant use of azole anti-fungals and inhaled fluticasone propionate. Therefore, care is advised when co-administering potent cytochrome P450 3A4 inhibitors (e.g. ketoconazole) as there is potential for increased systemic exposure to fluticasone propionate.

Drug-Drug Interactions

Table 2 Established or Potential Drug-Drug Interactions

Legend: CT = Clinical Trial; PM = Post-marketing; T = Theoretical

DOSAGE AND ADMINISTRATION

Dosing Considerations

The lowest dose of FLOVENT(r) (fluticasone propionate) required to maintain good asthma control should be used. When the patient's asthma is well controlled, a reduction in the dose of FLOVENT(r) should be attempted in order to identify the lowest possible dose required to maintain control. Such an attempt at dose reduction should be carried out on a regular basis.

Patients using inhaled bronchodilators should be advised to use the bronchodilator before the FLOVENT(r) in order to enhance the penetration of FLOVENT(r) into the bronchial tree. Several minutes should lapse between the use of the two inhalers to allow for some bronchodilation to occur. In the presence of excessive mucous secretion, the drug may fail to reach the bronchioles. Therefore, if an obvious response is not obtained after ten days, a short course of systemic corticosteroid treatment might be in order. Continuation of treatment with inhaled fluticasone propionate usually maintains the improvement achieved, the systemic steroid being gradually withdrawn. Treatment with FLOVENT(r) should not be stopped abruptly, but tapered off gradually. Physicians should be aware that, due to the improved potency of FLOVENT(r), the dose may be different than that required with some other inhaled steroids.

Recommended Dose and Dosage Adjustment

The dosage of FLOVENT(r) should be adjusted according to individual response. For patients whose asthma has been stabilized without the use of a spacer device, continuation of therapy with a spacer may require a dosage adjustment.

Adults and adolescents 16 years of age and older

Usual dosage is 100 to 500 micrograms twice daily. Patients should be given a starting dose of FLOVENT(r) which is appropriate for the severity of their disease (see Indications section) as follows:

The dose may then be adjusted until control is achieved or reduced to the minimum effective dose according to the individual response. Alternatively, the starting dose of FLOVENT(r) may be gauged at half the total daily dose of beclomethasone dipropionate or equivalent as administered by metered-dose inhaler (see Clinical Trials section). Onset of effect occurs within 4 - 7 days, although some benefit may be apparent as soon as 24 hours of the start of treatment with FLOVENT(r) for patients who have not previously received inhaled steroids. If no improvement is noted in this time frame, an increase in dose should be considered.

Children 4-16 years of age

The usual starting dose is 50 or 100 micrograms twice daily and many children's asthma will be well controlled with this regimen. For those patients whose asthma is not sufficiently controlled, additional benefit may be obtained by increasing the FLOVENT(r) DISKUS(r) dose up to 200 micrograms twice daily. Children should be given a starting dose of inhaled fluticasone propionate which is appropriate for the severity of their disease. The dose should be adjusted until control is achieved or reduced to the minimum effective dose according to the individual response. This is particularly important in the younger children with severe symptoms who are receiving the larger daily dose. The lowest dose of FLOVENT(r) HFA inhalation aerosol available is 50 mcg; therefore, it does not offer the required lowest pediatric dose, in which case an alternative inhalation device of FLOVENT(r) should also be considered (e.g. dry powder inhaler).

Children 12 months to 4 years of age

Younger children should be given 100 micrograms twice daily administered via a pediatric spacer device with a face mask such as a BABYHALER(r). Clinical trials in 12 month to 4 year old children have shown that the optimal control of asthma symptoms is achieved with 100 micrograms twice daily. Higher doses of inhaled drug are required in younger children compared to older children because of reduced efficiency of drug delivery due to smaller airways, use of a spacer device and increased nasal breathing. The diagnosis and treatment of asthma should be kept under regular review.

Special patient groups

There is no need to adjust the dose in elderly patients or those with hepatic or renal impairment.

Patients receiving systemic steroids

The transfer of steroid-dependent patients to FLOVENT(r), and their subsequent management, needs special care mainly because recovery from impaired adrenocortical function, caused by prolonged systemic therapy, is slow. Patients' bronchial asthma should be stable before being given FLOVENT(r) in addition to the usual maintenance dose of systemic steroid. After about a week, gradual withdrawal of the systemic steroid is started by reducing the daily dose by 1.0 milligram of prednisone, or its equivalent of other corticosteroid, at not less than weekly intervals, if the patient is under close observation. In children, the usual rate of withdrawal is 1.0 milligram of the daily dose of prednisone every eight days when under close supervision. If continuous supervision is not feasible, the withdrawal of the systemic steroid should be slower, approximately 1.0 milligram of the daily dose of prednisone (or equivalent) every ten and every twenty days in adults and in children, respectively. A slow rate of withdrawal cannot be over- emphasized. If withdrawal symptoms appear, the previous dose of the systemic drug should be resumed for a week before any further decrease is attempted. Patients who have been treated with systemic steroids for long periods of time or at a high dose may have adrenocortical suppression. In these patients adrenocortical function should be monitored regularly and their dose of systemic steroid reduced cautiously. Some patients feel unwell during the withdrawal phase experiencing symptoms such as joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement of respiratory function. Such patients should be encouraged to persevere with FLOVENT(r) but should be watched carefully for objective signs of adrenal insufficiency such as hypotension and weight loss. If evidence of adrenal insufficiency occurs, the systemic steroid dosage should be boosted temporarily and thereafter further withdrawal should be continued more slowly.

Transferred patients whose adrenocortical function is impaired should carry a warning card indicating that they need supplementary treatment with systemic steroids during periods of stress, e.g. surgery, chest infection, or severe asthma attack. Consideration should be given to supplying such patients with oral steroids to use in an emergency. The dose of inhaled fluticasone propionate should be increased at this time and then reduced to the maintenance level after the systemic steroid has been discontinued. Exacerbations of bronchial asthma which occur during the course of treatment with FLOVENT(r) should be treated with a short course of systemic steroid which is gradually tapered as these symptoms subside. Under stressful conditions or when the patient has a severe exacerbation of bronchial 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 dosage should be given in addition to FLOVENT(r).

Missed Dose

If a single dose is missed, instruct the patient to take the next dose when it is due.

Administration

FLOVENT(r) HFA inhalation aerosol and DISKUS(r) are to be administered by oral inhalation only. Patients must be instructed, as described in the PART III CONSUMER INFORMATION section, in the correct method of using FLOVENT(r) HFA inhalation aerosol or DISKUS(r) to ensure that the drug reaches the target areas within the lungs. Since the effect of FLOVENT(r) depends on its regular use and on the proper technique of inhalation, the patient should be made aware of the prophylactic nature of therapy with inhaled fluticasone propionate, and that for optimum benefit FLOVENT(r) should be taken regularly even when the patient is asymptomatic. As a general rule, rinsing the mouth and gargling with water after each inhalation can help in preventing the occurrence of candidiasis. Cleansing dentures has the same effect.

Inhalation Aerosol

Before the first use of FLOVENT(r) HFA inhalation aerosol and after periods of greater than seven days without use, the inhaler should be primed before treatment by actuating the inhaler once. Inhalation aerosol actuation should be synchronised with inspiration to ensure optimum delivery of drug to the lungs. The use of the open-mouth technique to administer FLOVENT(r) HFA inhalation aerosol has not been investigated in clinical trials.

DISKUS(r)

FLOVENT(r) DISKUS(r) is a device for delivering the dry powder formulation of fluticasone propionate. When using FLOVENT(r) DISKUS(r), the usual prescribed dose is one blister (inhalation) twice a day.

OVERDOSAGE

Acute inhalation of FLOVENT(r) (fluticasone propionate) doses in excess of those approved may lead to temporary suppression of the hypothalamic-pituitary-adrenal axis. This does not usually require emergency action, as normal adrenal function typically recovers within a few days. If higher than approved doses are continued over prolonged periods, significant adrenocortical suppression is possible. There have been very rare reports of acute adrenal crisis occurring in children exposed to higher than approved dosages (typically 1000 mcg daily and above), over prolonged periods (several months or years); observed features included hypoglycemia and sequelae of decreased consciousness and/or convulsions. Situations which could potentially trigger acute adrenal crisis include exposure to trauma, surgery or infection or any rapid reduction in dosage. Patients receiving higher than approved dosages should be managed closely and the dose reduced gradually. Chronic use of inhaled fluticasone propionate in daily doses in excess of the recommended dosage may lead to some degree of adrenal suppression. Monitoring of adrenal reserve may be indicated. Gradual reduction of the inhaled dose may be required. Treatment with inhaled FLOVENT(r) should be continued at a dose sufficient to control asthma. For management of a suspected drug overdose, contact your regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

FLOVENT(r) (fluticasone propionate) is a highly potent glucocorticoid anti-inflammatory steroid. When administered by inhalation at therapeutic dosages it has direct potent anti- inflammatory action within the lungs, resulting is reduced symptoms and exacerbations of asthma and less adverse effects than systemically administered corticosteroids. In comparison with beclomethasone dipropionate, fluticasone propionate has demonstrated greater topical potency.

Pharmacodynamics

Fluticasone propionate has many pharmacokinetic and pharmacodynamic features similar to those of other inhaled glucocorticoids used for the treatment of asthma. However, in contrast to these other steroids, a combination of incomplete gastrointestinal absorption and high first pass metabolic extraction ensures that virtually no fluticasone propionate swallowed after oral inhalation reaches the systemic circulation (see Detailed Pharmacology section).

Pharmacokinetics

Following intravenous administration, the pharmacokinetics of fluticasone propionate are proportional to dose. Fluticasone propionate is extensively distributed within the body. The volume of distribution at steady state is approximately 300 litres and had a very high clearance which is estimated to be 1.1 litre/minute indicating extensive hepatic extraction. Peak plasma fluticasone propionate concentrations are reduced by approximately 98% within 3-4 hours and only low plasma concentrations are associated with the terminal half-life, which is approximately 8 hours. Following oral administration of fluticasone propionate, 87-100% of the dose is excreted in the faeces. Following doses of either 1 or 16 mg, up to 20% and 75% respectively, is excreted in the faeces as the parent compound. There is a non-active major metabolite. Absolute oral bioavailability is negligible (<1%) due to a combination of incomplete absorption from the gastrointestinal tract and extensive first-pass metabolism. Following inhaled dosing in healthy volunteers, absolute systemic bioavailability of fluticasone propionate varies between approximately 10-30% of the nominal dose depending on the inhalation device used. Systemic absorption of fluticasone propionate occurs mainly through the lungs, and is initially rapid then prolonged. The plasma protein binding of fluticasone propionate is 91%. Fluticasone propionate is extensively metabolised by the CYP3A4 enzyme to an inactive carboxylic acid derivative.

STORAGE AND STABILITY

Inhalation Aerosol

Replace the mouthpiece cover firmly and snap it into position. Store at room temperature (15degC to 30degC). Protect from frost and direct sunlight.

DISKUS(r)

Store between 2degC and 30degC in a dry place. Protect from frost and direct sunlight.

SPECIAL HANDLING INSTRUCTIONS

Inhalation Aerosol

Contents under pressure. Container may explode if heated. Do not place in hot water or near radiators, stoves, or other sources of heat. Even when apparently empty, do not puncture or incinerate container or store at temperatures over 30OC. As with most inhaled medications in pressurised canisters, the therapeutic effect of this medication may decrease when the canister is cold.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Inhalation Aerosol

FLOVENT(r) HFA (fluticasone propionate) inhalation aerosol is a pressurized metered- dose inhaler (MDI) consisting of an aluminum canister fitted with a metering valve. Each canister is fitted into the supplied orange actuator/adaptor. A dust cap is fitted over the actuator's mouthpiece when not in use. FLOVENT(r) HFA inhalation aerosol comprises a suspension of fluticasone propionate in the propellant, 1,1,1,2-tetrafluoroethane (HFA-134a). FLOVENT(r) HFA inhalation aerosol is available in three strengths: 50 mcg/actuation, 125 mcg/actuation, or 250 mcg/actuation. The 50 mcg strength of FLOVENT(r) HFA inhalation aerosol is available in 120 dose containers. The 125 mcg and 250 mcg strengths of FLOVENT(r) HFA inhalation aerosol are available in 60 and 120 dose containers. This product does not contain chlorofluorocarbons (CFCs) as the propellant.

DISKUS(r)

FLOVENT(r) DISKUS(r) (fluticasone propionate) is a plastic inhaler device containing a foil strip with 60 blisters. Each blister contains 50, 100, 250, or 500 mcg of the active ingredient fluticasone propionate. It also contains lactose (milk sugar), including milk protein, which acts as the "carrier".

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: fluticasone propionate Chemical name: s-fluoromethyl 6a, 9a-difluoro-11b-hydroxy-16a-methyl-3-oxo- 17a-propionyloxyandrosta-1,4-diene-17b-carbothioate Molecular formula and molecular mass: C25H31F3O5S 500.6 Structural formula:

HO

CH3

CH3 H

COSCH2F

OCOC2H5 CH3

F H

O

F

Physicochemical properties: Description: Fluticasone propionate is a white to off-white powder. It is freely soluble in dimethyl sulfoxide and dimethylformamide, sparingly soluble in acetone, dichloromethane, ethyl acetate and chloroform, slightly soluble in methanol and 95% ethanol, and practically insoluble in water. Fluticasone propionate decomposes without melting. Onset of decomposition occurs at about 225OC.

CLINICAL TRIALS

Fluticasone Propionate in Adults, Adolescents and Children

There have been very rare reports of anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability (predominantly in children and adolescents). Four studies in adults and children have compared the effect of FLOVENT(r) (fluticasone propionate) at half the daily dose of beclomethasone dipropionate over the whole range of asthma severity (see Table below).

Table 3 Summary of Comparative Trials of Fluticasone Propionate versus Twice the Daily Dose of Other Inhaled Corticosteroids.

* primary efficacy parameter = morning PEF (= indicates similar efficacy, > indicates significantly greater

efficacy)

+

mean morning plasma cortisol levels (= indicates similar cortisol levels, > indicates significantly higher cortisol levels)

FP = fluticasone propionate

BDP = beclomethasone dipropionate

Throughout this dose range (i.e. 200-1000 mcg daily), fluticasone propionate at half the dose of beclomethasone dipropionate resulted in at least as great or greater increase in morning PEF, the primary efficacy parameter, as well as at least equal or greater reduction in secondary efficacy parameters such as symptom scores and rescue bronchodilator use. In the paediatric study, the increase in mean percent predicted PEF was significantly greater with fluticasone propionate 200 mcg daily than with beclomethasone dipropionate 400 mcg. These data demonstrate at least equal efficacy with fluticasone propionate compared with twice the dose of beclomethasone dipropionate over the whole range of asthma severity. Moreover, in the above 4 studies, comparing fluticasone propionate with beclomethasone dipropionate, the mean plasma cortisol levels, both basal and stimulated, were either the same or significantly higher after fluticasone propionate, indicating less HPA-axis suppression and suggesting an improved therapeutic ratio. In all studies in symptomatic patients, fluticasone propionate improved PEF compared with baseline or placebo. In 2 clinical trials using a 1:1 dose ratio in 373 severe asthmatic patients, fluticasone propionate was significantly more effective than beclomethasone dipropionate at equal doses. In addition, the improvement in lung function was maintained over 12 months. In clinical trials in over 1300 asthmatic children, fluticasone propionate Rotadisk 50 mcg bid (100 mcg/day) and 100 mcg bid (200 mcg/day) and fluticasone propionate inhaler 100 mcg bid (200 mcg/day) are effective in the treatment of childhood asthma. In one of these clinical studies with 225 asthmatic children, daily doses of fluticasone propionate at 100 mcg/day demonstrated significantly greater efficacy than sodium cromoglycate given at 80 mg/day. In another clinical trial in 398 asthmatic children, doses of 200 mcg/day fluticasone propionate were equal to or more effective than beclomethasone dipropionate given at 400 mcg/day. Onset of improvement occurred within 4-7 days of the start of treatment with fluticasone propionate. In a 12-week study in 274 adult patients with severe asthma, those receiving fluticasone propionate demonstrated an improvement in morning PEF of over 20 L/min above baseline by day 7. An equivalent increase of 20 L/min was achieved after at least 4 weeks in patients receiving beclomethasone dipropionate. The rapid onset of efficacy of fluticasone propionate was reflected in a reduced incidence of asthma exacerbations when fluticasone propionate was given at half the dose of beclomethasone dipropionate in 3 short-term (4- to 6-week) clinical trials in 1000 mild, moderate and severe asthmatics. The rate of asthma exacerbations was low for both treatments and similar on each treatment, although the ratio of doses (fluticasone propionate:beclomethasone dipropionate) was 1:2. The number of patients with at least one exacerbation of asthma remained constant over 12 months of treatment in two high dose studies in severe asthma. Approximately 70-75% of patients with severe asthma from these 2 studies were exacerbation-free after 12 months of treatment with high-dose fluticasone propionate. Throughout the clinical trial programme, mean serum cortisol levels for both adults and children remained within the normal range for up to 12 months across the dosage range. After 12 months treatment at 2000 mcg/day, suppression of HPA-axis occurred in approximately 7% of asthma patients. Clinical trials were conducted to investigate the use of fluticasone propionate 200 mcg twice daily in children aged 4 years and over, whose asthma is not sufficiently controlled. More than 1,800 asthmatic children aged 4-16 years were studied in controlled trials. Results have shown statistically significant increases in lung function for fluticasone propionate 200 mcg twice daily compared with the study comparator. A long term study (52 weeks) conducted in children aged 4-9 showed that treatment with fluticasone propionate 200 mcg twice daily was associated with significantly higher growth rate compared with budesonide dipropionate 200 mcg twice daily. Assessments of HPA-axis function, although variable, gave no clinical evidence of significant adrenal suppression or reduction in cortisol levels during any treatment and therefore were not considered by the investigators to be of clinical relevance or cause for concern. There was no evidence to suggest that long-term exposure of fluticasone propionate 200 mcg twice daily for up to 12 months caused any unfavourable effects in terms of adverse events.

Clinical Trials conducted with FLOVENT(r) HFA

A multicentre, randomized, double-blind study was conducted in children 4 to 16 years of age to assess the efficacy and safety of FLOVENT(r) HFA compared to the CFC formulation of fluticasone propionate. The results of the study demonstrated comparable efficacy between FLOVENT(r) HFA and the CFC formulation over a 4-week period (90% confidence limits for the difference between treatments were contained within +- 15L/min for mean morning PEF). The results from Clinic Visit FEV1, percentage predicted Clinic Visit FEV1, Clinic Visit PEF and percentage predicted PEF were similar between treatments, showing improvement from baseline. The adverse event profile was similar for both treatment groups and no new or unexpected adverse events were observed. In a randomized, multicentre, double-blind, placebo-controlled trial involving 160 pre- school children aged 12 months to 4 years of age, who exhibited persistent chronic asthma symptoms, treatment with fluticasone propionate 100 mcg twice daily via a pediatric spacer device demonstrated a statistically significant difference between treatment groups in favour of fluticasone propionate in the percentage of symptom-free 24-hour periods (including cough and wheeze) (p=0.035) over the 12-week treatment period. In addition, FLOVENT(r) HFA showed similar tolerability and adverse event profile compared to placebo. A long-term study (52 weeks) conducted in preschool children aged 12 months to 4 years of age showed that treatment with FLOVENT(r) HFA 100 mcg twice daily via a pediatric spacer device was associated with a statistically significant difference in the percentage of symptom-free days (p<0.001) and percentage of days with no rescue medication (p=0.023) compared to sodium cromoglycate. Growth rate was not affected over the 52- week treatment period by fluticasone propionate treatment compared to sodium cromoglycate treatment. No differences were apparent for the height velocities when analyzed according to sex or age. A reduction in cortisol levels was observed in subjects treated with fluticasone propionate; however, this was not considered by the investigators to be of clinical significance. The nature and incidence of adverse events were similar in both treatment groups. A three-month, prospective, post-marketing, observational cohort study was carried out to actively monitor the safety of the introduction of FLOVENT(r) HFA, into general practice in England, during the transition period from FLOVENT(r) CFC to FLOVENT(r) HFA. The primary comparison was of event rates, as recorded by the prescribing GP, in the three months before and the three months after first exposure to FLOVENT(r) HFA. The final cohort consisted of 13,413 patients. Of these, 1381 (10.3%) received FLOVENT(r) HFA 50 mcg per inhalation; 5992 (44.7%) 125 mcg per inhalation and 6040 (45.0%) 250 mcg per inhalation. 2683 patients (20%) were age 16 years and under. There were no statistically significant differences in event reported pre-exposure compared to post-exposure. Less than 10% of the total cohort stopped using FLOVENT(r) HFA within the 3 month study period. The most common reasons for stopping were "condition improved" and "other drug substituted". Overall, the results suggest that the transition to FLOVENT(r) HFA was well tolerated.

DETAILED PHARMACOLOGY

FLOVENT(r) (fluticasone propionate) was shown to be approximately twice as potent in topical activity as beclomethasone dipropionate according to the McKenzie vasoconstrictor assay. In human volunteers, fluticasone propionate was 9.5 times more potent than fluocinolone acetonide and intermediate in potency between betamethasone-17-valerate (less potent) and clobetasol-17-propionate (more potent). Although relative vasoconstrictor activity does not necessarily imply similar relative therapeutic efficacy, evidence for local anti-inflammatory action without systemic effects has been demonstrated by studies in laboratory animals and confirmed in human clinical pharmacology studies.

Animal

Animal studies of the relative anti-inflammatory and hypothalamic-pituitary-adrenal (HPA) axis inhibitory potencies of topically applied drug demonstrated that fluticasone propionate has an advantageous therapeutic index (>200 times that of beclomethasone dipropionate). Studies in rodents were conducted to quantify and compare anti-inflammatory activity after topical administration of fluticasone propionate and the ability to produce specific systemic steroid-related effects after topical, oral or parenteral administration. Topical anti-inflammatory activity was measured in rats and mice using the inflammatory response to croton oil applied topically to the ear. Results showed that fluticasone propionate was essentially equipotent with fluocinolone acetonide in both rats and mice. Systemic responses to repeated topical applications of fluticasone propionate were assessed by measurement of thymus involution and reduction in stress-induced plasma corticosterone (HPA axis suppression) in rats and mice, and adrenal atrophy in the rat. In these tests fluticasone propionate was 50-100 fold less potent than fluocinolone acetonide in the rat (56-fold greater therapeutic index) and 100 times less potent than fluocinolone acetonide in mice (relative therapeutic index 91). Therefore, in both species, the separation between topical anti-inflammatory and systemic activity after topical application, was highly favourable to fluticasone propionate. Comparison of systemic activity after topical and subcutaneous dosing of fluticasone propionate shows that, in both rats and particularly in mice, fluticasone propionate is more potent when given subcutaneously. In rats, fluticasone propionate given subcutaneously was compared with betamethasone alcohol and fluocinolone acetonide using thymus involution, adrenal atrophy, and inhibition of carrageenan granuloma formulation as assessments of systemic activity. Fluticasone propionate was equipotent with betamethasone alcohol and between 13 and 38 times less potent than fluocinolone acetonide. In mice, using thymus involution and HPA axis suppression, fluticasone propionate given subcutaneously, was approximately equipotent with betamethasone alcohol and approximately 4 times less potent than fluocinolone acetonide. After oral dosing in rats, fluticasone propionate caused some thymus involution, adrenal atrophy and HPA axis suppression but was 6 to 38 times less potent than betamethasone alcohol. In the mouse, oral fluticasone propionate is 60 to 200 times less potent than betamethasone alcohol. Two dogs received 1 mg fluticasone propionate by inhalation daily for 3 days. Marked suppression of plasma cortisol concentrations and adrenal function occurred which only began to recover 7 days after the final dose. The total dose given was approximately 110 mcg/kg/day, which is approximately 3 times higher than the maximum recommended inhaled daily dose (2000 mcg). Fluticasone propionate was screened for a wide range of steroid hormonal or anti- hormonal activity. To ensure significant systemic exposure, fluticasone propionate was administered subcutaneously to rats and mice and was found to be devoid of androgenic, anabolic, oestrogenic, and anti-gonadotrophic activity. Fluticasone propionate had some progestational activity in oestrogen-primed weanling rabbits, and also showed some anti- androgenic and anti-oestrogenic activity. Weak anti-anabolic activity, another characteristic of potent glucocorticoids, was observed in the castrated rat. Fluticasone propionate lacked mineralocorticoid activity but caused significant diuresis and urinary excretion of sodium and potassium. Propellant HFA-134a is devoid of pharmacological activity except at very high doses in animals (140 to 800 times the maximum human exposure based on comparisons of AUC values), primarily producing ataxia, tremors, dyspnea, or salivation. These are similar to effects produced by the structurally related CFCs, which have been used extensively in metered-dose inhalers.

Pharmacokinetics

Pharmacokinetic data from rats, dogs and humans indicate that clearance is high relative to hepatic blood flow. Consequently, first-pass metabolism is extensive and oral bioavailability is negligible (<1% in man). Studies examining the distribution of radiolabelled fluticasone propionate in the rat have shown that orally administered drug is absorbed and then excreted in the bile on first-pass through the liver. Thus only minute traces of radioactivity pass into the systemic circulation. Inhalational administration to rats involves a significant ingestion of dose, with subsequent excretion via the faeces. Direct pulmonary dosing in dogs involved higher systemic exposure to fluticasone propionate. The vast majority of a radiolabelled dose following intravenous (rat and dog), oral and subcutaneous (mouse, rat and dog) administration is excreted via the faeces, and evidence from bile-duct cannulated animals indicates that the major route of excretion is via the bile. Renal excretion is of minor importance, as urinary excretion accounts for less than 5% of a parenteral dose. No unchanged drug is excreted in the bile of rats or dogs, but a significant amount (up to 40%) of unchanged compound was found in the faeces of dogs dosed orally with fluticasone propionate. Thus, the low oral bioavailability of fluticasone propionate expected due to extensive first-pass metabolism is compounded by incomplete absorption from the gastrointestinal tract, particularly in the dog. The major route of metabolism in rats, dogs and humans is the hydrolysis of the fluorinated carbothioate group to yield the inactive carboxylic acid. When administered orally to pregnant rats (100 mcg/kg) or rabbits (300 mcg/kg), a very small fraction of the dose (<0.005%) passes across the placenta. Following inhaled doses of 2000 mcg per day (1000 mcg twice daily) for 14 days in healthy volunteers, peak plasma concentrations of about 0.3 ng/mL were observed at 30- 60 minutes post-dosing. Following inhaled dosing in healthy volunteers, systemic bioavailability of fluticasone propionate is estimated as 10-30% depending on the presentation. Since the bioavailability of the swallowed portion of an inhaled dose which reaches the gastrointestinal tract is virtually zero, the systemic absorption would be a reflection of the amount of drug reaching the lungs. Fluticasone propionate has many pharmacokinetic and pharmacodynamic features similar to those of other inhaled glucocorticoids used for the treatment of asthma. However, in contrast to these other steroids, a combination of incomplete gastrointestinal absorption and high first pass metabolic extraction ensures that virtually no fluticasone propionate swallowed after oral inhalation reaches the systemic circulation. Studies with radiolabelled and unlabelled fluticasone propionate administered orally to human volunteers indicate that the majority of the dose (87-100%) is excreted in the faeces, with up to 75% as unchanged drug, depending on the dose administered. Between 1% and 5% of the dose is excreted as metabolites in urine. Single oral doses of 16 mg in healthy volunteers produced plasma levels of less than 0.5 ng/mL. Single intravenous doses of 2 mg in healthy volunteers revealed that the clearance of fluticasone propionate approximates liver blood flow (900 mL/min), with renal clearance (0.11 mL/min) accounting for less than 1%. These results indicate that hepatic extraction is almost complete and that oral bioavailability is close to zero. Following intravenous administration, the pharmacokinetics of fluticasone propionate are proportional to the dose. Fluticasone propionate is extensively distributed within the body. The volume of distribution at steady state is approximately 300 litres and has a very high clearance which is estimated to be 1.1 litre/minute indicating extensive hepatic extraction. Peak plasma fluticasone propionate concentrations are reduced by approximately 98% within 3-4 hours and only low plasma concentrations are associated with the terminal half-life, which is approximately 8 hours. In animals and humans, propellant HFA-134a was eliminated rapidly in the breath, with no evidence of metabolism or accumulation in the body. Time to maximum plasma concentration (tmax) and mean residence time are both extremely short, leading to a transient appearance of HFA-134a in the blood with no evidence of accumulation.

TOXICOLOGY

Toxicology studies conducted with FLOVENT(r) (fluticasone propionate) have shown only those class effects typical of potent corticosteroids, and these have occurred only at doses greatly in excess of that proposed for therapeutic use. No novel effects were identified in repeat dose toxicity tests, reproductive studies, or teratology studies. Fluticasone propionate is devoid of mutagenic activity in vitro and in vivo and showed no tumorigenic potential in rodents. It is both non-irritant and non-sensitizing in animal models. The non-CFC propellant, HFA134a, has been shown to have no toxic effect at very high vapour concentrations, far in excess of those likely to be experienced by patients, in a wide range of animal species exposed daily for periods of two years.

Acute Toxicity

The results of the acute toxicity studies with fluticasone propionate, administered by inhalation, orally, subcutaneously and intravenously, demonstrated a large margin of safety over the anticipated maximum daily exposure in humans of 2000 mcg/day. The approximate LD50 values are shown in the following table:

Table 4 Acute Toxicity Studies with Fluticasone Propionate in Animals

High oral doses of 1 g/kg were well tolerated in both the mouse and rat. The only (reversible) changes observed were a slowing in growth rate and microscopically-evident cortical depletion of the thymus of animals killed 3 days after dosing. Subcutaneous doses of fluticasone propionate at 1 g/kg were administered to mice and rats. Animals progressively lost condition and body weight and the effects seen were thymic depletion and various lesions associated with a compromised immune system. In addition, gastric steroid ulcers were seen. These observed changes are the expected response to glucocorticoid therapy. The lack of reversible thymic effects in subcutaneously dosed animals is almost certainly due to the deposition and leaching of insoluble steroid from the injection site. When given intravenously to rats at a dose of 2 mg/kg, the only changes seen were slightly subdued behaviour immediately after treatment and reversible thymic involution. Acute administration of the complete contents of a 200 metered-dose inhaler of fluticasone propionate to dogs (approx. 0.82 mg/kg) produced no effects of toxicological significance.

Chronic Toxicity Studies

Subacute toxicity studies were conducted in adult and juvenile rats for periods up to 35 days and in Beagle dogs for periods up to 44 days. Fluticasone propionate was administered as follows:

Table 5 Chronic Toxicity Studies with Fluticasone Propionate in Animals

* maximum dose of fluticasone propionate administered

Clinical observations were similar for all routes of administration in both species. These consisted of reduced weight gain and general loss of condition. Inhalation studies in the dog resulted in clinical signs associated with the administration of a potent glucocorticoid and consistent with the symptoms of Canine Cushing's Syndrome. Changes typical of glucocorticoid overdosage were seen in both haematological and clinical chemistry parameters. Effects were seen on the red cell parameters and a characteristic leukopenia resulting from a lymphopenia accompanied by a neutrophilia. Endogenous cortisol and corticosterone were depressed in dogs and rats, respectively. Microscopic pathology was again consistent with the administration of a potent glucocorticoid showing thymic and adrenal atrophy, lymphoid depletion in rats and dogs and glycogenic vacuolation of the liver in dogs. There was no change or evidence of irritancy attributable to fluticasone propionate in the respiratory tract in any of the inhalation studies. There were no specific effects on the maturation of juvenile rats after subcutaneous dosing. Chronic inhalation toxicity studies using fluticasone propionate were conducted for up to 18 months in rats, using snout-only exposure. In two 6 month studies, rats received doses of up to 80 mcg/kg/day; the maximum daily dose administered during the 18 month study was 57 mcg/kg. Changes seen in haematological, biochemical and urinalysis parameters were those typical of glucocorticoid overdosage. Histological findings included lymphoid depletion and thymic and adrenal atrophy. There was at least partial regression of all clinical changes either during the treatment period or within the recovery period. At all dose levels the observed changes were considered to have arisen directly or indirectly from the immunomodulatory or physiological actions of a corticosteroid. None of these changes was of pathological significance. Inhalation studies with fluticasone propionate of up to 12 months duration were also conducted in dogs. In one 6 month study, doses of fluticasone propionate administered were 60, 150 or 450 mcg/animal/day, while in the second study, groups received 68, 170 or 510 mcg/animal/day. In a third study, dogs received 7.5, 18 or 50.7 mcg/animal/day for 12 months. The most commonly observed dose-related clinical signs were characteristic corticosteroid effects consisting of poor coat and/or skin condition, increased hair loss, loose faeces, distended abdomen and obesity. Haematological and biochemical parameters were typical of glucocorticoid overdosage and consisted of a moderate to marked leukopenia and lymphopenia and increased erythrocytes, serum enzymes, protein and cholesterol. Dose-related histopathological changes consisted of thymic involution, adrenal atrophy, lymphoid depletion in lymph nodes and spleen, and glycogenic infiltration of the liver. No histopathological changes were seen in the respiratory tract after inhalation of fluticasone propionate. Most of the fluticasone propionate-induced changes showed a rapid regression after cessation of treatment by inhalation. Some symptoms persisted throughout the recovery period after subcutaneous administration probably due to prolonged release of fluticasone propionate from subcutaneous depots. Two dogs (510 mcg/day group, 26 weeks) died of opportunistic infections as a result of reduced immunocompetence arising from excess corticosteroid administration.

Mutagenicity

Fluticasone propionate did not induce gene mutation in prokaryotic microbial cells, and there was no evidence of toxicity or gene mutational activity in eukaryotic Chinese hamster cells in vitro. The compound did not induce point mutation in the Fluctuation assay, and did not demonstrate gene convertogenic activity in yeast cells. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro, and fluticasone propionate was not demonstrably clastogenic in the mouse micronucleus test when administered at high doses by oral or subcutaneous routes. Furthermore, the compound did not delay erythroblast division in bone marrow.

Reproduction and Teratology

Subcutaneous studies in the mouse and rat at 150 and 100 mcg/kg/day, respectively, revealed maternal and foetal toxicity characteristic of potent glucocorticoid compounds, including reduction in maternal weight gain, embryonic growth retardation, increased incidences of retarded cranial ossification, and of omphalocoele and cleft palate in rats and mice, respectively. In the rabbit, subcutaneous doses of 30 mcg/kg/day and above were incompatible with sustained pregnancy. This is not unexpected since rabbits are known to be particularly sensitive to glucocorticoid treatment. These parenteral doses are up to 5 times the recommended maximum human inhaled dose (2000 mcg/day). Following oral administration of fluticasone propionate up to 300 mcg/kg to the rabbit, there were no maternal effects nor increased incidence of external, visceral, or skeletal foetal defects. A very small fraction (<0.005%) of the dose crossed the placenta following oral administration to rats (100 mcg/kg/day) and rabbits (300 mcg/kg/day).

Carcinogenicity

No treatment-related effects were observed on the type or incidence of neoplasia in a 18 month oral (gavage) study in mice administered fluticasone propionate at dose levels of up to 1 mg/kg/day. In a lifetime (2 years) snout-only inhalation study in rats, at dose levels of up to 57 mcg/kg/day, there was an increase in the incidence of tumours in the mammary gland, liver and pancreas. These were not considered as evidence of tumorigenic effect of fluticasone propionate based on the absence of statistical support of an increase in incidence and the historical tumour incidence data.

Local Tolerance

Intranasal administration of fluticasone propionate aqueous nasal spray to cynomolgus monkeys for 28 days at 400 mcg/day did not cause local irritancy to the nasal cavity or respiratory tract, or systemic toxicity. Micronised fluticasone propionate was considered to be non-irritating in the rabbit eye when assessed using a modified Draize test and, in the guinea pig split adjuvant test for evaluating contact sensitivity, results were completely negative. Acute eye irritancy tests conducted with 1000 mcg of fluticasone propionate inhalation aerosol in the rabbit showed no effect on the conjunctiva, cornea, or iris.

REFERENCES

1. Alexander DJ, Libretto SE. An overview of the toxicology of HFA-134a (1,1,1,2- tetrafluoroethane). Hum Exp Toxicol 1995; 14(9):715-720.

2. Allen DB, Bronsky EA, LaForce CF, Nathan RA, Tinkelman DG, Vandewalker ML et al. Growth in asthmatic children treated with fluticasone propionate. Fluticasone Propionate Asthma Study Group. J Pediatr 1998; 132(3 Pt 1):472- 477.

3. Barnes NC, Marone G, Di Maria GU, Visser S, Utama I, Payne SL. A comparison of fluticasone propionate, 1 mg daily, with beclomethasone dipropionate, 2 mg daily, in the treatment of severe asthma. International Study Group. Eur Respir J 1993; 6(6):877-885.

4. Brutsche MH, Brutsche IC, Munawar M, Langley SJ, Masterson CM, Daley- Yates PT et al. Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers: a randomised crossover study. Lancet 2000; 356(9229):556-561.

5. Dahl R, Lundback B, Malo JL, Mazza JA, Nieminen MM, Saarelainen P et al. A dose-ranging study of fluticasone propionate in adult patients with moderate asthma. International Study Group. Chest 1993; 104(5):1352-1358.

6. Daley-Yates PT, Tournant J, Kunka RL. Comparison of the systemic availability of fluticasone propionate in healthy volunteers and patients with asthma. Clin Pharmacokinet 2000; 39 Suppl 1:39-45.

7. Essellier AF, Jeanneret RL, Morandi L. The mechanism of glucocorticoid eosinopenia; contribution to the physiology of eosinophile granulocytes. Blood 1954; 9(5):531-549.

8. Fabbri L, Burge PS, Croonenborgh L, Warlies F, Weeke B, Ciaccia A et al.

Comparison of fluticasone propionate with beclomethasone dipropionate in moderate to severe asthma treated for one year. International Study Group. Thorax 1993; 48(8):817-823. Gustafsson P, Tsanakas J, Gold M, Primhak R, Radford M, Gillies E. Comparison of the efficacy and safety of inhaled fluticasone propionate 200 micrograms/day with inhaled beclomethasone dipropionate 400 micrograms/day in mild and moderate asthma. Arch Dis Child 1993; 69(2):206-211. Harding SM. The human pharmacology of fluticasone propionate. Respir Med 1990; 84 Suppl A:25-29. Hoffmann-Streb A, L'Allemand D, Niggemann B, Buttner P, Wahn U. [Adrenal cortex function in children with bronchial asthma in fluticasone therapy]. Monatsschr Kinderheilkd 1993; 141(6):508-512. Langdon CG, Capsey LJ. Fluticasone propionate and budesonide in adult asthmatics: A comparison using dry-powder inhaler devices. Br J Clin Res 1994; 5:85-99. Langdon CG, Thompson J. A multicentre study to compare the efficacy and safety of inhaled fluticasone propionate and budesonide via metered-dose inhalers in adults with mild-to-moderate asthma. Br J Clin Res 1994; 5:73-84. Leaf A. Ozone depletion and public health. Hosp Pract (Off Ed) 1994; 29(6):9-10. Leblanc P, Mink S, Keistinen T, Saarelainen PA, Ringdal N, Payne SL. A comparison of fluticasone propionate 200 micrograms/day with beclomethasone dipropionate 400 micrograms/day in adult asthma. Allergy 1994; 49(5):380-385. Li JT, Ford LB, Chervinsky P, Weisberg SC, Kellerman DJ, Faulkner KG et al. Fluticasone propionate powder and lack of clinically significant effects on hypothalamic-pituitary-adrenal axis and bone mineral density over 2 years in adults with mild asthma. J Allergy Clin Immunol 1999; 103(6):1062-1068. Lundback B, Alexander M, Day J, Hebert J, Holzer R, Van Uffelen R et al. Evaluation of fluticasone propionate (500 micrograms day-1) administered either as dry powder via a Diskhaler inhaler or pressurized inhaler and compared with beclomethasone dipropionate (1000 micrograms day-1) administered by pressurized inhaler. Respir Med 1993; 87(8):609-620. Lyttle BD, Gillies J, Panov M, Emeryk A, Wixon C. Equivalent efficacy and safety in children of CFC-free fluticasone propionate (GR106642X) via a pressurised metered dose inhaler compared with the current CFC (P11/12) inhaler. Am J Respir Crit Care Med 1999; 159(3 PART 2):909. MacKenzie CA, Weinberg EG, Tabachnik E, Taylor M, Havnen J, Crescenzi K. A placebo controlled trial of fluticasone propionate in asthmatic children. Eur J Pediatr 1993; 152(10):856-860. Mckenzie AW, Stoughton RB. Method of comparing percutaneous absorption of steroids. Arch 1962; 86:608-610. Mckenzie AW, Atkinson RM. Topical activities of Betamethasone Esters in man. Arch Dermatol 1964; 89:741-746. Ninan TK, Reid IW, Carter PE, Smail PJ, Russell G. Effects of high doses of inhaled corticosteroids on adrenal function in children with severe persistent asthma. Thorax 1993; 48(6):599-602. Pauwels RA, Yernault JC, Demedts MG, Geusens P. Safety and efficacy of fluticasone and beclomethasone in moderate to severe asthma. Belgian Multicenter Study Group. Am J Respir Crit Care Med 1998; 157(3 Pt 1):827-832. Perrechoud AP, Jones AL. A three month multi-national study comparing the efficacy and safety of fluticasone propionate propelled by chlorofluorocarbons 11 and 12 or by a CFC-free propellant, GR106642X, in adults. Eur Respir J 1995; 8(suppl.#19):abs. no. P0841. Schardein JL. Drugs as teratogens. CRC Press Inc 1976; 217-228. Skidmore IF. Anti-inflammatory steroids. The pharmacological and biochemical basis of clinical activity. Molecular Aspects of Medicine 1981; 4:303-327. Stoughton RB. Bioassay system for formulations of topically applied glucocorticosteroids. Arch Dermatol 1972; 106(6):825-827. Sykes AP, Huskisson SC. Overall tolerability of fluticasone propionate (FP) pressurised metered dose inhaler formulated with a new CFC-free propellant (GR106642X). Eur Respir J 1997; 10(SUPPL. 25):127S. Sykes AP, Huskisson SC. The incidence of acute affects when switching between pressurised metered-dose inhalers (MDI) formulated with CFC and CFC-free propellants. Am J Respir Crit Care Med 1998; 157(3):A635. Szefler SJ, Boushey HA, Pearlman DS, Togias A, Liddle R, Furlong A et al. Time to onset of effect of fluticasone propionate in patients with asthma. J Allergy Clin Immunol 1999; 103(5 Pt 1):780-788. Ventresca GP. Clinical pharmacology of HFA 134a. Journal of aerosol medicine: the official journal of the International Society for Aerosols in Medicine 1995; 8(supp.1):s35. Wolthers OD, Pedersen S. Short-term growth during treatment with inhaled fluticasone propionate and beclomethasone dipropionate. Arch Dis Child 1993; 68(5):673-676.

PART III: CONSUMER INFORMATION

PrFLOVENT(r) HFA

fluticasone propionate inhalation aerosol

This leaflet is part III of a three-part "Product Monograph" for FLOVENT(r) HFA inhalation aerosol and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about FLOVENT(r) HFA inhalation aerosol. Contact your doctor or pharmacist if you have any questions about the drug. This medicine is for you. Only a doctor can prescribe it for you. Never give it to someone else. It may harm them even if their symptoms are the same as yours.

ABOUT THIS MEDICATION

What the medication is used for:

FLOVENT(r) HFA inhalation aerosol is a medicine which your doctor will have chosen to suit you and your condition.

FLOVENT(r) HFA inhalation aerosol helps breathing problems in people who need regular treatment.

Asthma is a chronic inflammatory disease of the lungs characterized by episodes of difficulty in breathing. People with asthma have extra sensitive or "twitchy" airways. During an asthma attack the airways react by narrowing, making it more difficult for the air to flow in and out of the lungs.

Control of asthma requires avoiding irritants that cause asthma attacks and taking the appropriate medications. For example, patients should avoid exposure to house dust mites, mold, pets, tobacco smoke and pollens.

What it does:

Fluticasone propionate is one of a group of medicines called corticosteroids used to treat breathing problems because they

have an anti-inflammatory action. They reduce the swelling and irritation in the walls of the small air passages in the lungs

and so ease breathing problems. Corticosteroids also help to

• Do not use if you have moderate to severe bronchiectasis (a lung condition).

What the medicinal ingredient is:

FLOVENT(r) HFA inhalation aerosol contains fluticasone propionate.

What the important nonmedicinal ingredients are: FLOVENT(r) HFA inhalation aerosol is suspended in a CFC- free propellant, HFA.

What dosage forms it comes in:

FLOVENT(r) HFA inhalation aerosol is a pressurized metered dose inhaler containing 50, 125, or 250 mcg of fluticasone

propionate per inhalation.

WARNINGS AND PRECAUTIONS

Tell your doctor before using FLOVENT(r) HFA inhalation aerosol:

If you have ever had to stop taking other medicines for this illness because you were allergic to them or they caused problems.

If you have ever had a yeast infection (thrush) in your mouth.

If you have a history of tuberculosis (TB) infections.

If you are taking other "steroids" by mouth or inhalation.

If you are suffering from any chest infection (e.g. cold, bronchitis).

If you are suffering from diabetes.

If you are pregnant or breastfeeding.

If you notice the following warning signs, you should contact a physician as soon as possible or go to the nearest hospital.

A sudden worsening of your shortness of breath and wheezing shortly after using your fast-acting

prevent attacks of asthma.

relief medication or after using FLOVENT

inhalation aerosol.

HFA

When it should not be used:

Do not use if you are allergic or have had an allergic reaction to fluticasone propionate or any of the ingredients in this medication (see what the important non medicinal ingredients are).

Do not use this medicine to treat a sudden attack of breathlessness. You will probably need a different kind of medicine in a different colour pack which your doctor may already have given you. If you have more than one medicine, be careful not to confuse them.

Do not use if you have a fungal, bacterial or tuberculous infection, unless advised by your doctor.

• You do not feel relief within 10 minutes after using your fast-acting relief medication or the relief does not last for at least 3 hours.

• Measurement from your peak flow meter indicates a value less than 60 percent of predicted or personal best.

• You are breathless at rest.

• Your pulse is more than 120 beats per minute.

If you experience the following symptoms, inform your doctor immediately as they may indicate that your asthma is getting worse and your treatment may need to be reassessed.

• A change in your symptoms such as more coughing, attacks of wheezing, chest tightness, or an unusual increase in the severity of the breathlessness.

• You wake up at night with chest tightness, wheezing or shortness of breath.

• You use increasing amounts of your fast-acting relief medication.

• Measurement from your peak flow meter indicates a value between 60 to 80% of predicted or personal best.

After you start taking FLOVENT(r) HFA inhalation aerosol, your doctor may change the dosages of your other asthma medicines. Rarely, this may make a patient feel worse rather than better. This especially applies to oral corticosteroids, including prednisone. If your doctor decreases your oral steroid dose, and you become unwell, tell your doctor immediately.

INTERACTIONS WITH THIS MEDICATION

Drugs that may interact with FLOVENT(r) HFA inhalation aerosol include: Ritonavir (a medicine used to treat HIV infection or AIDS) and azole antifungals (e.g. ketoconazole). Make sure that your doctor knows what other medicines you are taking (such as those for allergies, nervousness, depression, migraine, etc. ), including those you can buy without a prescription as well as herbal and alternative medicines.

PROPER USE OF THIS MEDICATION

How to use your FLOVENT(r) HFA inhalation aerosol properly:

It is important that you take each dose as instructed by your doctor, nurse, or pharmacist. Your doctor will decide which strength of FLOVENT(r) HFA inhalation aerosol you should use.

Before you use your FLOVENT(r) HFA inhalation aerosol for the first time, or if your inhaler has not been used for a week or more, shake it well and release one puff into the air to ensure that it works properly.

Use FLOVENT(r) HFA inhalation aerosol only with the actuator supplied with the product. Discard canister after 60 sprays have been used for the 60 dose canister or

120 sprays for the 120 dose canister.

1. To remove the snap-on mouthpiece cover, hold between the thumb and forefinger, squeeze gently and pull apart as shown. Check inside and outside of the inhaler including the mouthpiece for the presence of loose objects.

2. Shake the inhaler well to ensure that any loose objects are removed and that the contents of the inhaler are evenly mixed.

3. Hold the inhaler upright between fingers and thumb with your thumb on the base, below the mouthpiece. Breathe out as far as comfortable.

4. Place the mouthpiece in your mouth between your teeth and close your lips around it, but do not bite it. Just after starting to breathe in through your mouth, press firmly down on the top of the inhaler to release the drug while still breathing in steadily and deeply.

5. While holding your breath, take the inhaler from your mouth and take your finger from the top of the inhaler. Continue holding your breath for about 10 seconds or for as long as is comfortable.

6. If you are to take further puffs, keep the inhaler upright and wait about half a minute before repeating steps 2 through 5.

7. Replace the mouthpiece cover by firmly pushing and snapping the cap into position to keep out dust and lint.

8. Rinse out your mouth and gargle with water after each dose. Do not swallow the water after rinsing and gargling.

Important

Do not rush steps 4 and 5. It is important that you start to

breathe in as slowly as possible just before operating your inhaler. Practice in front of a mirror for the first few times. If you see "mist" coming from the top of your inhaler or the sides of your mouth, you should start again from step 2.

If your doctor has given you different instructions for using the inhaler, please follow them carefully. Tell your doctor if you have any difficulties.

Each prescribed dose is usually given by a minimum of 2 inhalations.

Children/Elderly:

Some children may need help and an adult may need to operate the inhaler for them. Encourage the child to breathe

out and operate the inhaler just after the child starts to breathe in. Practice the technique together. Children or people with

weak hands should hold the inhaler with both hands. Put the

two forefingers on top of the inhaler and both thumbs on the base below the mouthpiece.

If using a spacer device such as BABYHALER(r), follow the manufacturer's instructions.

Cleaning:

To prevent your inhaler from blocking up, it is important to

clean it at least once a week, following the instructions below. If your inhaler does block up, the same cleaning instructions should be followed. If you notice a build-up of medicine around the mouthpiece, do not attempt to unblock it with a sharp object, such as a pin.

To clean your inhaler:

1. Remove the mouthpiece cover.

2. Do not remove the canister from the plastic casing.

3. Wipe the inside and outside of the mouthpiece and the plastic casing with a dry cloth, tissue or cotton swab. Do not put the metal canister into water.

4. Replace the mouthpiece cover.

5. After cleaning, release one puff into the air to make sure that the inhaler works.

Usual dose:

It may take several days for this medicine to work and it is

very important that you use it regularly

. If your shortness of breath or wheeze does not get better in 7 days, tell your doctor.

Do not stop taking FLOVENT(r) HFA suddenly - even if you feel better. Your doctor can provide you with information about how to slowly stop the medication if necessary. Do not take more doses or use your inhaler more often than your doctor advises. If you have to go into hospital for an operation, take your inhaler with you and tell the doctor what medicine(s) you are taking. If your doctor decides to stop treatment, do not keep any left-over medicine unless your doctor tells you to.

Talk to your doctor before using FLOVENT(r) HFA inhalation aerosol with a spacer device (holding chamber) because your dose may need to be changed.

Adults and Adolescents 16 years or older

The usual dose is 100 to 500 micrograms twice daily. Patients with very severe asthma, requiring higher doses of

corticosteroids such as those patients currently requiring oral steroids may use doses up to 1000 micrograms twice daily.

Children 4-16 years

The usual dose is 50 to 100 micrograms twice daily to a maximum of 200 micrograms daily.

Children 12 months to 4 years

The usual dose is 100 micrograms twice daily, administered by

device.

Overdose:

In the event of an excessive overdose (more than the maximum recommended daily dose), tell your doctor without delay or

contact your nearest hospital emergency department or poison centre.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Missed Dose:

It is very important that you use FLOVENT(r) HFA inhalation aerosol regularly; however, if you miss a single

dose, do not worry - just take the next dose when it is due.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Very occasionally, some people find that their throat or tongue becomes sore after taking this medicine or that their voice becomes a little hoarse. In some people, a yeast infection of the mouth and throat called candidiasis (thrush) may occur. Tell your doctor but do not stop treatment unless told to do so.

Rinsing your mouth and gargling with water immediately after taking each dose may help. Do not swallow the water after rinsing. Cleaning dentures may also help.

It is possible that some patients, especially those taking higher doses of this type of medication, may very rarely suffer from the following side effects: rounded face, loss of bone density, eye problems and slowing of growth in children. Some people may experience increased bruising. These effects are much less likely to occur than with steroid tablets. It is very important that you use your medicine regularly to control your asthma.

Very rarely the person taking the medicine may feel anxious, have disturbed sleep or notice behavioural changes including hyperactivity and irritability (mainly in children and adolescents).

The treatment may cause an increase in the amount of sugar (glucose) in your blood. If you have diabetes, this may cause an upset in your blood sugar control. More frequent blood sugar monitoring and possibly adjustment of your usual diabetes treatment may be required.

The following events were reported in children but may not be related to the drug: upper respiratory tract infection, cough, rhinitis (itchy/runny nose, congestion and/or sneezing), headache, fever, throat irritation and asthma.

Medicines affect different people in different ways. Just because side effects have occurred in other patients does not mean you will get them. If any side effects bother you, please contact your doctor.

Store FLOVENT(r) HFA inhalation aerosol at room temperature (15degC to 30degC). Protect from frost and direct sunlight.

As with most inhaled medications in pressurized canisters, the effect of this medication may decrease when the canister is cold. If the inhaler becomes very cold, remove the metal canister and warm it in your hand for a few minutes. Never use other forms of heat.

Warning

- The metal canister is pressurized. Do not puncture it, even when you think it is empty.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance:

By toll-free telephone: 866-234-2345 By toll-free fax: 866-678-6789

Online: www.healthcanada.gc.ca/medeffect By email: CanadaVigilance @hc-sc.gc.ca

By regular mail:

Canada Vigilance National Office

Marketed Health Products Safety and Effectiveness Information Bureau

Marketed Health Products Directorate Tunney's Pasture, AL 0701C

Ottawa ON K1A 0K9

NOTE: Should you require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.

This is not a complete list of side effects. For any unexpected effects while taking FLOVENT(r) HFA inhalation aerosol, contact your doctor or pharmacist.

HOW TO STORE IT

Keep your medicine in a safe place where children cannot reach it. Your medicine may harm them.

After use, replace the mouthpiece cover firmly and snap it into position. Do not use excessive force.

MORE INFORMATION

You may need to read this package insert again. Please do not throw it away until you have finished your medicine. This document plus the full product monograph, prepared for health professionals can be found at:

http://www.gsk.ca

or by contacting the sponsor, GlaxoSmithKline Inc.,

7333 Mississauga Road Mississauga, Ontario L5N 6L4

1-800-387-7374.

This leaflet was prepared by GlaxoSmithKline Inc. Last revised: August 08, 2008

(c)

2008 GlaxoSmithKline Inc. All Rights Reserved

(r)

FLOVENT and BABYHALER are registered trademarks, used under license by GlaxoSmithKline Inc.

PART III: CONSUMER INFORMATION

PrFLOVENT(r) DISKUS(r)

fluticasone propionate powder for inhalation

This leaflet is part III of a three-part "Product Monograph" for FLOVENT(r) DISKUS(r) and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about FLOVENT(r) DISKUS(r). Contact your doctor or pharmacist if you have any questions about the drug. This medicine is for you. Only a doctor can prescribe it for you. Never give it to someone else. It may harm them even if their symptoms are the same as yours.

ABOUT THIS MEDICATION

What the medication is used for:

FLOVENT(r) DISKUS(r) is a medicine which your doctor will have chosen to suit you and your condition. FLOVENT(r)

DISKUS(r) helps breathing problems in people who need

regular treatment.

Asthma is a chronic inflammatory disease of the lungs characterized by episodes of difficulty in breathing. People with asthma have extra sensitive or "twitchy" airways. During an asthma attack the airways react by narrowing, making it more difficult for the air to flow in and out of the lungs.

Control of asthma requires avoiding irritants that cause asthma attacks and taking the appropriate medications. For example, patients should avoid exposure to house dust mites, mold, pets, tobacco smoke and pollens.

What it does:

Fluticasone propionate is one of a group of medicines called corticosteroids used to treat breathing problems because they

have an anti-inflammatory action. They reduce the swelling

and irritation in the walls of the small air passages in the lungs and so ease breathing problems. Corticosteroids also help to prevent attacks of asthma.

When it should not be used:

• Do not use if you are allergic or have had an allergic reaction to fluticasone propionate or any of the ingredients in this medication, including lactose (see what the important non medicinal ingredients are).

• Do not use this medicine to treat a sudden attack of breathlessness. You will probably need a different kind of medicine in a different colour pack which your doctor may already have given you. If you have more than one medicine be careful not to confuse them.

• Do not use if you have a fungal, bacterial or tuberculous infection, unless advised by your doctor.

• Do not use if you have moderate to severe bronchiectasis (a lung condition).

What the medicinal ingredient is:

FLOVENT(r) DISKUS(r) contains fluticasone propionate.

What the important nonmedicinal ingredients are: FLOVENT(r) DISKUS(r) contains lactose (milk sugar), and milk protein, which act as the 'carrier'.

What dosage forms it comes in:

FLOVENT(r) DISKUS(r) is a dry powder inhalation device that delivers 50, 100, 250, or 500 mcg of fluticasone propionate per

inhalation.

WARNINGS AND PRECAUTIONS

Tell your doctor before using FLOVENT(r) DISKUS(r):

If you have ever had to stop taking other medicines for this illness because you were allergic to them or they caused problems.

If you have been told you are allergic to lactose (milk sugar) or milk protein.

If you have ever had a yeast infection (thrush) in your mouth.

If you have a history of tuberculosis (TB) infections.

If you are taking other "steroids" by mouth or inhalation.

If you are suffering from any chest infection

(e.g. cold, bronchitis).

If you are suffering from diabetes.

If you are pregnant or breastfeeding.

If you notice the following warning signs, you should contact a physician as soon as possible or go to the nearest hospital.

A sudden worsening of your shortness of breath and wheezing shortly after using your fast-acting relief medication or after using FLOVENT(r) DISKUS(r).

You do not feel relief within 10 minutes after using your fast-acting medication or the relief does not last for at least 3 hours.

Measurement from your peak flow meter indicates a value less than 60 percent of predicted or personal best.

You are breathless at rest.

Your pulse is more than 120 beats per minute.

If you experience the following symptoms, inform your doctor immediately as they may indicate that your asthma is getting worse and your treatment may need to be reassessed.

A change in your symptoms such as more coughing, attacks of wheezing, chest tightness, or an unusual increase in the severity of the breathlessness.

You wake up at night with chest tightness, wheezing or shortness of breath.

You use increasing amounts of your fast-acting relief medication.

Measurement from your peak flow meter indicates a value between 60 to 80% of predicted or personal best.

After you start taking FLOVENT(r) DISKUS(r), your doctor may change the dosages of your other asthma medicines. Rarely, this may make a patient feel worse rather than better. This especially applies to oral corticosteroids, including prednisone. If your doctor decreases your oral steroid dose, and you become unwell, tell your doctor immediately.

INTERACTIONS WITH THIS MEDICATION

Drugs that may interact with FLOVENT(r) DISKUS(r) include: Ritonavir (a medicine used to treat HIV infection or AIDS) and azole antifungals (e.g. ketoconazole). Make sure that your doctor knows what other medicines you are taking (such as those for allergies, nervousness, depression, migraine, etc. ), including those you can buy without a prescription as well as herbal and alternative medicines.

PROPER USE OF THIS MEDICATION

How to use your FLOVENT(r) DISKUS(r) properly: About your FLOVENT(r) DISKUS(r)

FLOVENT(r) DISKUS(r) is a plastic inhaler device containing a

foil strip with 60 blisters. Each blister contains 50, 100, 250 or 500 micrograms of the active ingredient fluticasone propionate. It also contains lactose (milk sugar), including

milk protein, which acts as the "carrier". The blisters protect

the powder for inhalation from the effects of the atmosphere. When you take your FLOVENT(r) DISKUS(r) out of its box, it will be in the closed position.

A new DISKUS(r) contains 60 individually protected doses of your medicine, in powder form. The device has a dose counter which tells you the number of doses remaining. It counts down from 60 to 1. To show when the last five doses have been reached the numbers appear red.

Each dose is accurately measured and hygienically protected. It requires no maintenance, and no refilling.

How your FLOVENT(r) DISKUS(r) works:

The FLOVENT(r) DISKUS(r) is easy to use. When you need a dose, just follow the four simple steps illustrate:

1.Open, 2. Slide, 3. Inhale, 4. Close.

Sliding the lever of your DISKUS(r) opens a small hole in the mouthpiece and unwraps a dose ready for you to inhale it. When you close the DISKUS(r), the lever automatically moves back to its original position ready for your next dose when you need it. The outer case protects your DISKUS(r) when it is not in use.

1. Open

To open your DISKUS(r) hold the outer case in one hand and put the thumb of your other hand on the thumb grip. Push your thumb away

from you as far as it will go.

Slide

Hold your DISKUS(r) with the mouthpiece towards you. Slide the lever away from you as far as it will go - until it clicks. Your

DISKUS(r) is now ready to use. Every time the

lever is pushed back a dose is made available for inhaling. This is shown by the dose counter. Do not play with the lever as this releases doses which will be wasted.

Inhale

Before you start to inhale the dose, read through this section carefully.

Hold the DISKUS(r) away from your mouth.

Breathe out as far as is comfortable. Remember - never exhale into your DISKUS(r).

Put the mouthpiece to your lips. Breathe in steadily and deeply - through the DISKUS(r), not through your nose.

Remove the DISKUS(r) from your mouth. Hold your breath for about 10 seconds or for as long as is comfortable.

Breathe out slowly.

Close

To close your DISKUS(r), put your thumb in the thumb grip, and slide the thumb grip back

towards you, as far as it will go.

When you close the DISKUS(r), it clicks shut. The lever automatically returns to its original

position and is reset. Your DISKUS(r) is now

ready for you to use again.

Rinse out your mouth and gargle with water after each dose. Do not swallow the water after rinsing and gargling.

If you have been instructed to take two inhalations you must close the DISKUS(r) and repeat stages 1 to 4.

Remember

Keep your DISKUS(r) dry. Keep it closed when not in use.

Never exhale into your DISKUS(r). Only slide the lever when you are ready to take a dose.

Usual dose:

It may take up to a week for this medicine to work and it is

very important that you use it regularly. If your shortness of breath or wheeze does not get better in 7 days, tell your doctor. Do not stop taking FLOVENT(r) DISKUS(r) suddenly - even if you feel better. Your doctor can provide you with information about how to slowly stop the medication if necessary. Do not take more doses or use your FLOVENT(r) DISKUS(r) more often than your doctor advises. The medicine in FLOVENT(r) DISKUS(r) must not be swallowed but should only be inhaled. If you have to go into hospital for an operation, take your FLOVENT(r) DISKUS(r) with you and tell the doctor what medicine(s) you are taking. If your doctor decides to stop treatment, do not keep any left-over medicine unless your doctor tells you to.

Adults and Adolescents 16 years or older

The usual dose is in the range of 100 to 500 micrograms twice daily. Patients with very severe asthma, requiring higher

doses of corticosteroids such as those patients currently

requiring oral steroids may use doses up to 1000 micrograms twice daily.

Children 4-16 years

The usual dose is 50 to 100 micrograms twice daily. For those patients whose asthma is not sufficiently controlled,

additional benefit may be obtained by increasing the dose up to 200 micrograms twice daily.

Overdose:

In the event of an excessive overdose (more than the

maximum recommended daily dose), tell your doctor without delay or contact your nearest hospital emergency department or poison centre.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Missed Dose:

It is very important that you use FLOVENT(r) DISKUS(r) regularly; however, if you miss a single dose, do not worry -

just take the next dose when it is due.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Very occasionally, some people find that their throat or tongue becomes sore after taking this medicine or that their voice becomes a little hoarse. In some people, a yeast infection of the mouth and throat called candidiasis (thrush) may occur. Tell your doctor but do not stop treatment unless told to do so. Rinsing your mouth and gargling with water immediately after taking each dose may help. Do not swallow the water after rinsing. Cleaning dentures may also help.

It is possible that some patients, especially those taking higher doses of this type of medication, may very rarely suffer from the following side effects: rounded face, loss of bone density, eye problems and slowing of growth in children. Some people may experience increased bruising. These effects are much less likely to occur than with steroid tablets.

It is very important that you use your medicine regularly to control your asthma.

Very rarely the person taking the medicine may feel anxious, have disturbed sleep or notice behavioural changes, including hyperactivitiy and irritability (mainly in children and adolescents).

The treatment may cause an increase in the amount of sugar (glucose) in your blood. If you have diabetes, this may cause an upset in your blood sugar control. More frequent blood sugar monitoring and possibly adjustment of your usual diabetes treatment may be required.

The following events were reported in children but may not be related to the drug: upper respiratory tract infection, cough, rhinitis (itchy/runny nose, congestion and/or sneezing), headache, fever, throat irritation and asthma.

Medicines affect different people in different ways. Just because side effects have occurred in other patients does not mean you will get them. If any side effects bother you, please contact your doctor.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance:

By toll-free telephone: 866-234-2345 By toll-free fax: 866-678-6789

Online: www.healthcanada.gc.ca/medeffect By email: CanadaVigilance @hc-sc.gc.ca

By regular mail:

Canada Vigilance National Office

Marketed Health Products Safety and Effectiveness Information Bureau

Marketed Health Products Directorate Tunney's Pasture, AL 0701C

Ottawa ON K1A 0K9

This is not a complete list of side effects. For any unexpected effects while taking FLOVENT(r) DISKUS(r) inhalation aerosol, contact your doctor or pharmacist.

HOW TO STORE IT

Keep your medicine in a safe place where children cannot reach it. Your medicine may harm them.

Store between 2degC and 30degC in a dry place. Protect from frost and direct sunlight. Do not store in a damp environment such as a bathroom.

NOTE: Should you require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.

MORE INFORMATION

You may need to read this package insert again. Please do not throw it away until you have finished your medicine.

This document plus the full product monograph, prepared for health professionals can be found at:

http://www.gsk.ca

or by contacting the sponsor, GlaxoSmithKline Inc.

7333 Mississauga Road Mississauga, Ontario

L5N 6L4

1-800-387-7374.

This leaflet was prepared by GlaxoSmithKline Inc. Last revised: August 08, 2008

(c)

2008 GlaxoSmithKline Inc. All Rights Reserved

(r)FLOVENT and DISKUS are registered trademarks, used under license by GlaxoSmithKline Inc.