Flovent (Fluticasone Propionate)

FLOVENT®

Glaxo Wellcome

Fluticasone Propionate

Corticosteroid

Action And Clinical Pharmacology: Fluticasone is a highly potent glucocorticoid anti-inflammatory steroid with strong topical and negligible systemic activity. When administered by inhalation at therapeutic dosages, it has a direct potent anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma without the adverse effects observed when corticosteroids are administered systemically.

In comparisons with beclomethasone dipropionate, fluticasone propionate has demonstrated greater topical potency.

Pharmacokinetics: Following i.v. administration, the pharmacokinetics of fluticasone are proportional to the dose. Fluticasone is extensively distributed within the body. The volume of distribution at steady state is approximately 300 L and has a very high clearance which is estimated to be 1.1 L/min indicating extensive hepatic extraction. Peak plasma fluticasone concentrations are reduced by approximately 98% within 3 to 4 hours and only low plasma concentrations are associated with the terminal half-life, which is approximately 8 hours. Following oral administration of fluticasone, 87 to 100% of the dose is excreted in the feces. Following doses of either 1 or 16 mg, up to 20% and 75% respectively, is excreted in the feces as the parent compound. Absolute oral bioavailability is negligible.

Following inhaled dosing, systemic absolute bioavailability of fluticasone is estimated as 12 to 26%, dependent on presentation. Systemic absorption of fluticasone occurs mainly through the lungs, and is initially rapid, then prolonged.

The plasma protein binding of fluticasone propionate is 91%. Fluticasone is extensively metabolised by CYP3A4 enzyme to an inactive carboxylic acid derivative. As fluticasone is given at very low doses, any effect on coadministered drugs is unlikely. In clinical programmes, there were no reports of suspected drug interactions while patients were on inhaled fluticasone therapy.

The limited data available for pediatric pharmacokinetics show consistency with adult findings.

In most but not all patients, the daily output of adrenocortical hormones remain within the normal range during chronic treatment with inhaled fluticasone, even at the highest recommended doses in children (200 g/day) and adults (2 000 g/day). After transfer from other inhaled steroids to fluticasone propionate, the daily output gradually improves despite past and present intermittent use of oral steroids, thus demonstrating return of normal adrenal function on inhaled fluticasone. The adrenal reserve also remains normal during chronic treatment with inhaled fluticasone, as measured by a normal increment on a stimulation test. However, any residual impairment of adrenal reserve from previous treatments may persist for a considerable time and should be kept in mind (see Warnings and Precautions).

Indications And Clinical Uses: For the prophylactic management of steroid-responsive bronchial asthma in adults and children over 4 years of age.

Adults and Adolescents above 16 Years of Age: Mild Asthma: PEF values greater than 80% of predicted at baseline with less than 20% variability. Patients requiring intermittent symptomatic bronchodilator asthma medication on more than an occasional basis.

Moderate Asthma: PEF values 60 to 80% of predicted at baseline with 20 to 30% variability. Patients requiring regular asthma medication and patients with unstable or worsening asthma on currently available prophylactic therapy or bronchodilator alone.

Severe Asthma: PEF values less than 60% of predicted at baseline with greater than 30% variability. Patients with severe, chronic asthma. On introduction of inhaled fluticasone, many patients who are dependent on systemic corticosteroids for adequate control of symptoms may be able to reduce significantly or to eliminate their requirements for oral corticosteroids.

Severe asthma requires regular medical assessment as death may occur. Patients with severe asthma have constant symptoms and frequent exacerbations, with limited physical capacity. These patients will require high dose inhaled (see Dosage) or oral corticosteroid therapy. Sudden worsening of symptoms may require increased corticosteroid dosage which should be administered under urgent medical supervision.

Children above 4 Years of Age: For any child above 4 years of age who requires prophylactic medication, including patients not controlled on currently available prophylactic medication.

Contra-Indications: Patients with a history of hypersensitivity to any of its ingredients and in patients with active or quiescent pulmonary tuberculosis, or untreated fungal, bacterial or viral infections of the respiratory tract.

Not to be used in the primary treatment of status asthmaticus or other acute episodes of asthma, or in patients with moderate to severe bronchiectasis.

Manufacturers’ Warnings In Clinical States: 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, inhaled fluticasone 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 depression of plasma cortisol may occur in a small number of adult patients on higher doses (e.g., >1 mg/day). However, in most but not all patients, adrenal function and adrenal reserve remain within normal range on inhaled fluticasone therapy. 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.

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 fluticasone 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).

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 measurements 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 inhaled fluticasone 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 antihistamine and/or topical preparations, including topical steroids.

Candidiasis: Therapeutic dosages frequently cause the appearance of C. 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 out their mouths with water after using the inhaler. Symptomatic candidiasis can be treated with topical antifungal therapy while still continuing to use fluticasone.

Paradoxical Bronchospasm: 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. Fluticasone should be discontinued immediately, the patient assessed, and if necessary, alternative therapy instituted.

Monitoring Asthma Control: Increasing use of short-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.

Fluticasone is not indicated for rapid relief of bronchospasm but for regular daily treatment of the underlying inflammation. There is no evidence that control of bronchial asthma can be achieved by the administration of fluticasone in amounts greater than the recommended dosages.

Lack of response or severe exacerbations of asthma should be treated by increasing the dose of fluticasone and, if necessary, by giving a systemic steroid and/or an antibiotic if there is an infection.

Precautions: General: It is essential that the patients be instructed that fluticasone 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.

Systemic Steroid Replacement by Inhaled Steroid: 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, depression) may occur despite maintenance or improvement of respiratory function. The guidelines under Dosage should be followed in all such cases.

Long-term Effects: The long-term effects of fluticasone in human subjects are still unknown. In particular, 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. During long-term therapy, HPA axis function and hematological status should be assessed periodically.

Discontinuance: Treatment with fluticasone should not be stopped abruptly, but tapered off gradually.

Pulmonary Infiltration by Eosinophils: As with other glucocorticoids, pulmonary infiltration by eosinophils may occur in patients on fluticasone therapy. Although it is possible that in some patients this state may become manifest because of systemic steroid withdrawal when inhaled steroids are administered, a causative role for fluticasone and/or its vehicle cannot be ruled out.

Pregnancy: The safety of fluticasone 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 is teratogenic to rodent species. 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 fetal 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.

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

Children: Fluticasone is not presently recommended for children younger than 4 years of age due to limited clinical data in this age group.

Effect on Infection: Corticosteroids may mask some signs of infections and new infections may appear. A decreased resistance to localized infection has been observed during corticosteroid therapy. This may require treatment with appropriate therapy or stopping the administration of fluticasone until the infection is eradicated.

Abuse of Fluorocarbon Propellants: Fluorocarbon propellants may be hazardous if they are deliberately abused. Inhalation of high concentrations of aerosol sprays has brought about cardiovascular toxic effects and even death, especially under conditions of hypoxia. However, evidence attests to the safety of aerosols when used properly with adequate ventilation.

Hypothyroidism and Cirrhosis: There is an enhanced effect of corticosteroids on patients with hypothyroidism and in those with cirrhosis.

Corticosteroids and ASA: ASA should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia.

Proper Use of the Inhaler: To ensure the proper dosage and administration of the drug, the patient must be instructed by a physician or other health professional in the use of the Inhaler or Diskus (see Information for the Patient). Inhaler actuation should be synchronized with inspiration to ensure optimum delivery of the drug to the lungs.

Oral Hygiene: In some patients, corticosteroids may cause hoarseness or candidiasis of the mouth and throat (thrush). Adequate oral hygiene is of primary importance in minimizing overgrowth of microorganisms such as C. albicans. Patients may find it helpful to rinse out their mouth with water after using the inhaler (see Dosage). Symptomatic candidiasis can be treated with topical antifungal therapy while still continuing treatment with fluticasone.

Drug Interactions: No specific drug interaction studies have been performed; however, because of the very low plasma drug concentrations achieved after inhaled dosing, there are unlikely to be any implications for displacement drug interactions. There were no reports of suspected drug interactions in clinical trials with fluticasone.

Adverse Reactions: In general, inhaled corticosteroid therapy may be associated with dose dependent increases in the incidence of ocular complications, reduced bone density, suppression of HPA axis responsiveness to stress, and inhibition of growth velocity in children. Such events have been reported rarely in clinical trials with fluticasone.

Glaucoma may be exacerbated by inhaled corticosteroid treatment for asthma or rhinitis. In patients with established glaucoma who require long-term inhaled corticosteroid treatment, it is prudent to measure intraocular pressure before commencing the inhaled corticosteroid and to monitor it subsequently. In patients without established glaucoma, but with a potential for developing intraocular hypertension (e.g., the elderly), intraocular pressure should be monitored at appropriate intervals.

In elderly patients treated with inhaled corticosteroids, the prevalence of posterior subcapsular and nuclear cataracts is probably low but increases in relation to the daily and cumulative lifetime dose. Cofactors such as smoking, ultraviolet B exposure, or diabetes may increase the risk. Children may be less susceptible.

A reduction of growth velocity in children or teenagers may occur as a result of inadequate control of chronic diseases such as asthma or from use of corticosteroids for treatment. Physicians should closely follow the growth of adolescents taking corticosteroids by any route and weigh the benefits of corticosteroid therapy and asthma control against the possibility of growth suppression if any adolescent’s growth appears slowed.

Osteoporosis and fracture are the major complications of long-term asthma treatment with parenteral or oral steroids. Inhaled corticosteroid therapy is also associated with dose-dependent bone loss although the degree of risk is very much less than with oral steroid. This risk may be offset by estrogen replacement in postmenopausal women, and by titrating the daily dose of inhaled steroid to the minimum required to maintain optimal asthma control. It is not yet known whether the peak bone density achieved during youth is adversely affected if substantial amount of inhaled corticosteroid are administered prior to 30 years of age. Failure to achieve maximal bone density during youth could increase the risk of osteoporotic fracture when those individuals reach 60 years of age and older.

No major side effects attributable to the use of fluticasone have been reported. Adverse reactions in controlled clinical studies with fluticasone have been primarily those normally associated with asthma. Apart from asthma and related events and pharmacologically predicted events (candidiasis and hoarseness), there were no dose-related trends. Cutaneous hypersensitivity reactions have been observed. The adverse reactions reported by patients treated with fluticasone were similar to those reported by patients treated with beclomethasone dipropionate.

The most frequently reported adverse reactions (³1%) considered by the investigator to be potentially drug-related during controlled clinical trials with fluticasone in over 4 400 adults and 1 100 children are presented in Table I.

Infrequent adverse reactions (incidence of 0.1 to 1%) reported by patients receiving recommended dosages of inhaled fluticasone (200 to 2 000 µg/day for adults; 100 to 200 µg/day for children) in these clinical trials included headache, musculoskeletal pain, diabetes, hypertension, weight gain, viral infection, respiratory tract infection, nausea, gastric pain, allergy, depression and oral ulcer.

Adrenal Suppression: Studies in which adrenal reserve has been investigated have shown that even at daily dosages of fluticasone Inhaler greater than 1 mg, adrenal reserve is maintained in the majority of patients.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: The acute toxicity of fluticasone is low. The only harmful effect that follows inhalation of large amounts of the drug over a short period of time is suppression of adrenal function. No special emergency action need be taken. In such cases, treatment with inhaled fluticasone should be continued at a dose sufficient to control asthma; adrenal function recovers in a few days and can be verified by measuring plasma cortisol.

Chronic use of inhaled fluticasone in daily doses in excess of 2 mg 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 fluticasone should be continued at a dose sufficient to control asthma.

Dosage And Administration: General: The lowest dose of fluticasone required to maintain good asthma control should be used. When the patient’s asthma is well controlled, a reduction in the dose of fluticasone 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.

Fluticasone Inhaler and Diskus are to be administered by oral inhalation only.

Since the effect of fluticasone 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, and that for optimum benefit fluticasone should be taken regularly, even when the patient is asymptomatic. The onset of therapeutic effect is within 4 to 7 days.

If patients find that relief with short-acting bronchodilator treatment becomes less effective or they need more inhalations than usual, medical attention should be sought.

Patients using inhaled bronchodilators should be advised to use the bronchodilator before the fluticasone inhaler in order to enhance the penetration of fluticasone into the bronchial tree. Several minutes should lapse between the use of the 2 inhalers to reduce the potential toxicity from the inhaled fluorocarbon propellants and to allow for some bronchodilation to occur.

In the presence of excessive mucus secretion, the drug may fail to reach the bronchioles. Therefore, if an obvious response is not obtained after 10 days, attempts should be made to remove the mucus with expectorants and/or with a short course of systemic corticosteroid treatment. Continuation of treatment with inhaled fluticasone usually maintains the improvement achieved, the systemic steroid being gradually withdrawn.

As a general rule, rinsing the mouth and gargling after each inhalation with water can help in preventing the occurrence of candidiasis. Cleansing dentures has the same effect.

Treatment with fluticasone should not be stopped abruptly, but tapered off gradually.

Administration: Patients must be instructed, as described in Information for the Patient, in the correct method of using the Inhaler or Diskus to ensure that the drug reaches the target areas within the lungs.

Inhalers: When using the inhaler, each prescribed dose should be given by a minimum of 2 inhalations. Before the first use, and after a long period without use, the inhaler should be primed before treatment by actuating the inhaler 4 times.

Inhaler actuation should be synchronized with inspiration to ensure optimum delivery of drug to the lungs. In patients who find coordination of a pressurized metered dose inhaler difficult, a spacer device such as Vent-A-Haler may be used with the fluticasone inhaler.

Diskus: Flovent Diskus is a device for delivering the dry powder formulation of fluticasone. When using the Diskus, the usual prescribed dose is 1 blister (inhalation) twice a day.

The dosage of fluticasone should be adjusted according to individual response.

Adults: Usual dosage is 100 to 500 g twice daily.

Patients should be given a starting dose of inhaled fluticasone which is appropriate for the severity of their disease (see Indications) as follows: mild asthma: 100 to 250 g twice daily; moderate asthma: 250 to 500 g twice daily; severe asthma: 500 g twice daily. Very severe patients requiring higher doses of corticosteroids such as those patients currently requiring oral steroids may use doses up to 1 000 g twice daily.

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 fluticasone may be gauged at half the total daily dose of beclomethasone dipropionate or equivalent as administered by metered-dose inhaler. Onset of effect occurs within 4 to 7 days of the start of treatment with fluticasone. If no improvement is noted in this time frame, an increase in dose should be considered.

Adolescents: Above 16 years of age, the adult dosage applies.

Children (over 4 years of age): Children should be given a starting dose of inhaled fluticasone which is appropriate for the severity of their disease. This may be 50 or 100 µg twice daily. The dose may then be adjusted until control is achieved or reduced to the minimum effective dose according to the individual response.

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 inhaled fluticasone 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 inhaled fluticasone 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 mg 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 mg of the daily dose of prednisone every 8 days when under close supervision. If continuous supervision is not feasible, the withdrawal of the systemic steroid should be slower, approximately 1 mg of the daily dose of prednisone (or equivalent) every 10 and every 20 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 fluticasone 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 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 fluticasone 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 fluticasone.

Availability And Storage: Inhaler: Each actuation of metered-dose aerosol contains: fluticasone propionate (micronized) 25, 50, 125 or 250 g. Nonmedicinal ingredients: dichlorodifluoromethane, lecithin and trichlorofluoromethane. Aluminum canisters fitted with a metering valve of 60 and 120 doses. Each unit is housed in a suitable actuator/adaptor. Store between 2 and 30°C. Protect from frost and direct sunlight. 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 30°C. As with most inhaled medications in pressurized canisters, the therapeutic effect of this medication may decrease when the canister is cold.

Diskus: Each plastic inhaler device contains a foil strip with 60 blisters. Each blister contains: fluticasone propionate 50, 100, 250 or 500 g. Nonmedicinal ingredients: lactose, which acts as a “carrier”. Store between 2 and 30°C. Protect from frost and direct sunlight.

FLOVENT® Glaxo Wellcome Fluticasone Propionate Corticosteroid

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