Becloforte (Beclomethasone Dipropionate)

BECLOFORTE®

Glaxo Wellcome

Beclomethasone Dipropionate

Corticosteroid for the Treatment of Bronchial Asthma

Action And Clinical Pharmacology: Beclomethasone dipropionate is a potent anti-inflammatory steroid with strong topical and weak systemic activity. When inhaled at therapeutic dosages, it has a direct anti-inflammatory action on the bronchial mucosa. Since with therapeutic doses the minute amounts absorbed do not exert any significant systemic effect, inhaled beclomethasone dipropionate can replace oral steroids with the elimination of the untoward effects of systemic therapy.

Indications And Clinical Uses: Treatment of steroid-responsive bronchial asthma. Beclomethasone dipropionate can be used in 2 conditions: in bronchial asthmatic patients who in the past have not been on steroids, but whose condition requires inhaled beclomethasone dipropionate; in steroid-dependent patients to replace oral steroid medication with beclomethasone dipropionate through gradual withdrawal of the systemic steroid.

Becloforte is only to be used when the total daily dosage of beclomethasone dipropionate required is 500 to 1 000 µg.

Contra-Indications: Active or quiescent pulmonary tuberculosis, or fungal, bacterial and viral infections.

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

Also contraindicated in patients with a history of hypersensitivity to any of the ingredients of this preparation.

Manufacturers’ Warnings In Clinical States: Systemic Steroid Replacement by Inhaled Steroid: Particular care is needed in patients who are transferred from systemically active corticosteroids to beclomethasone dipropionate because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to aerosol beclomethasone dipropionate.

After withdrawal from systemic corticosteroids, a number of months is 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 beclomethasone dipropionate may provide control of asthmatic symptoms during these episodes, it does not provide the systemic steroid which is necessary for coping with these emergencies.

During periods of stress or a severe asthmatic attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume systemic steroids (in large dosages) 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. In the majority of patients no significant adrenal suppression occurs until doses of 1 500 µg/day, by inhalation, are exceeded. Reduction of plasma cortisol levels has been reported in some patients who received 2 000 µg/day of inhaled beclomethasone dipropionate. In such patients the risk of developing adrenal suppression should be balanced against the therapeutic advantages and precautions should be taken to provide systemic steroid cover in situations of prolonged stress. Prolonged suppression of the HPA axis may eventually lead to systemic effects including growth retardation in children and adolescents.

Transfer of patients from systemic steroid therapy to beclomethasone dipropionate may unmask allergic conditions 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.

Studies have shown that the combined administration of alternate-day prednisone systemic treatment and orally inhaled beclomethasone increases the likelihood of HPA suppression compared to a therapeutic dose of either one alone. Therefore, beclomethasone dipropionate treatment should be used with caution in patients already on alternate-day prednisone regimens for any disease.

Systemic Absorption of Orally Inhaled Steroids: Because of the possibility of systemic absorption of orally inhaled corticosteroids, including beclomethasone, patients should be monitored for symptoms of systemic effects such as mental disturbances, increased bruising, weight gain, cushingoid features, acneiform lesions and cataracts. If such changes occur, beclomethasone dipropionate should be discontinued slowly, consistent with accepted procedures for discontinuing oral steroids.

Candidiasis: The development of pharyngeal and laryngeal candidiasis is cause for concern because the extent of its penetration into the respiratory tract is unknown. These infections may require treatment with appropriate antifungal therapy and/or discontinuance of treatment with beclomethasone dipropionate, depending on the severity of the infections.

Monitoring Asthma Control: Beclomethasone dipropionate is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm. Patients will require a fast and short acting inhaled bronchodilator (e.g., salbutamol) to relieve acute asthmatic symptoms.

Patients should be instructed to contact their physicians immediately when episodes of asthma which are not responsive to bronchodilators occur during the course of treatment with Becloforte. During such episodes, patients may require therapy with systemic corticosteroids. There is no evidence that control of bronchial asthma can be achieved by the administration of beclomethasone dipropionate in amounts greater than the recommended dosages.

Precautions: It is essential that the patients be instructed that beclomethasone dipropionate is a preventative agent which must be taken daily at the intervals recommended by their doctor and is not to be used as acute treatment for an asthmatic attack.

Steroid Replacement by beclomethasone dipropionate: The replacement of a systemic steroid with beclomethasone dipropionate has to 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 beclomethasone dipropionate in human subjects are still unknown. In particular, the local effects of the agent 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 should not be stopped abruptly, but tapered off gradually.

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

Pregnancy: Unnecessary administration of drugs during the first trimester of pregnancy is undesirable. There is inadequate evidence of safety of beclomethasone dipropionate in human pregnancy. In animal reproduction studies adverse effects typical of potent corticosteroids are only seen at high systemic exposure levels; direct inhaled application ensures minimal systemic exposure. However, as with other drugs, the use of beclomethasone dipropionate during human pregnancy requires that the therapeutic benefits be weighed against the possible risks associated with the product. Infants born of mothers who have received substantial dosages of corticosteroids during pregnancy should be carefully observed for hypoadrenalism.

Lactation : Glucocorticoids are excreted in human milk. It is not known whether beclomethasone dipropionate would be excreted in human milk, but it is suspected to be likely. The use of beclomethasone dipropionate in pregnancy, nursing mothers, or women of childbearing potential requires that the possible benefits of the drug be weighed against the potential hazards to the mother, and embryo or fetus.

Teratogenic Effects: Glucocorticoids are known teratogens in rodent species and beclomethasone dipropionate is no exception.

Teratology studies done in rats, mice, and rabbits treated with s.c. beclomethasone dipropionate resulted in fetal resorptions, cleft palate, agnathia, microstomia, absence of tongue, delayed ossification, and partial agenesis of the thymus in both the mouse and rabbit. Well-controlled trials relating to fetal risk in humans are not available.

Effect on Infection: 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 nonimmune 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 affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled i.v. immunoglobulin (IVIG), as appropriate, may be indicated. If chickenpox develops, treatment with antiviral agents may be considered.

Corticosteroids may mask some signs of infections and new infections may appear. A decreased resistance to localized infection has been observed during corticosteroid therapy. During long-term therapy, pituitary-adrenal function and hematological status should be periodically assessed. Exacerbation of asthma caused by infections is usually controlled by appropriate antibiotic treatment, by increasing the dose of inhaled beclomethasone dipropionate and if necessary by giving a systemic steroid.

Abuse of Fluorocarbon Propellants: Fluorocarbon propellants may be hazardous if they are deliberately abused. Inhalation of high concentrations of aerosols 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 and 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 Drug: To ensure the proper dosage and administration of the drug, the patient must be instructed by a physician or other health professional in the proper use of the inhaler. Patients should be advised to inform subsequent physicians of the prior use of corticosteroids. Treatment with beclomethasone dipropionate should not be stopped abruptly, but tapered off gradually.

Oral Hygiene: Adequate oral hygiene is of primary importance in minimizing overgrowth of microorganisms such as C. albicans (see Dosage).

Adverse Reactions: General: 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.

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 increased 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 in 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 known yet whether the peak bone density achieved during youth is adversely affected if substantial amounts 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 these individuals reach 60 years of age and older.

Paradoxical Bronchospasm: As with other inhalation therapy, the potential for paradoxical bronchospasm should be kept in mind. If it occurs, the preparation should be discontinued immediately and alternative therapy instituted.

Adrenal Suppression: No indication of significant adrenal corticol suppression has been observed when the daily dosage was up to 1 mg (4 puffs). Above this dosage, reduction of plasma cortisol may occur.

Gastrointestinal Tract: Therapeutic dosages frequently cause the appearance of C. albicans in the mouth and throat. Long-term studies have shown a dosage-dependent effect. Positive cultures for oral Candida may be present in up to 75% of patients although the frequency of clinically apparent infection is considerably lower, varying between 0 and 43%, with an average of 15%. In some studies, an overgrowth of A. niger has been found in conjunction with C. albicans. Such affected patients may find it helpful to rinse their mouths with water after using Becloforte.

A few patients on beclomethasone dipropionate have complained of hoarseness, dry mouth or throat irritation. It may be helpful to rinse out the mouth with water immediately after inhalation.

Immunologic Reactions: The replacement of systemic steroids with beclomethasone dipropionate may unmask symptoms of allergies which were previously suppressed by the systemic drug. Conditions such as allergic rhinitis and eczema may thus become apparent during beclomethasone dipropionate therapy after the withdrawal of systemic corticosteroids.

Rare cases of immediate and delayed hypersensitivity reactions, including urticaria, angioedema, rash, and bronchospasm, have been reported after the use of beclomethasone oral or intranasal inhalers; pruritus, erythema, and edema of the eyes, face, lips and throat also have been reported.

Other Effects: Reports of headache, lightheadedness, dryness and irritation of the nose and throat, and unpleasant taste and smell have been received. There are rare reports of loss of taste and smell.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Acute: The acute toxicity of beclomethasone dipropionate is low. The only harmful effect that follows inhalation of large amounts of the drug over a short period of time is suppression of hypothalamic-pituitary-adrenal (HPA) function. No special emergency action need be taken. Treatment with beclomethasone dipropionate should be continued at the recommended dose to control the asthma; HPA function recovers in a day or two.

Chronic: The excessive use of beclomethasone dipropionate over a long period could lead to adrenal suppression. In such a case the patient should be transferred to oral corticosteroid therapy and when the condition has stabilized, be returned to inhaled therapy at the recommended dose. To guard against the unexpected event of adrenal suppression regular tests of adrenal function are advised. Oral steroids should then be slowly withdrawn, as for steroid-dependent patients.

Dosage And Administration: Becloforte is only to be used when the total daily dosage of beclomethasone dipropionate required is 500 to 1 000 µg.

Adults: One inhalation (250 µg) 2 to 4 times daily. Some patients may do well with 2 inhalations (500 µg) twice daily.

The total daily dosage should not exceed 1 mg of beclomethasone dipropionate (4 inhalations).

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

Children: Not recommended for children under 16 years of age.

General: 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.

Since the effect of Becloforte depends on its regular use and on the proper technique of inhalation, patients must be instructed to use their inhaler daily, as prescribed by their physician and not as with other aerosols, as they feel necessary. They must also be instructed in the correct method to use the Belcoforte inhalation aerosol which is described in the section Information for the Patient to ensure that the drug reaches the target areas within the lungs.

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 beclomethasone dipropionate usually maintains the improvement achieved, the oral steroid being gradually withdrawn.

Patients receiving bronchodilators by inhalation should be advised to use the bronchodilator before the beclomethasone dipropionate inhalation aerosol in order to enhance the penetration of beclomethasone dipropionate into the bronchial tree. Several minutes should elapse 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.

Patients Receiving Systemic Steroids: Careful attention must be given to patients previously treated for prolonged periods with systemic corticosteroids, when transferred to beclomethasone dipropionate. Patients’ bronchial asthma should be stable before transfer is started. Initially, Becloforte and the systemic steroid must be given concomitantly while the dosage of the latter is gradually decreased. In adults, the usual rate of withdrawal of the systemic corticosteroid is the equivalent of 1 mg of prednisone at no less than weekly intervals if the patient is under close observation. If continuous supervision is not feasible, the withdrawal of the systemic steroid should be slower, approximately 1 mg of prednisone (or equivalent) every 10 days. A slow rate of withdrawal cannot be overemphasized. If withdrawal symptoms appear, the previous dosage of the systemic drug should be resumed for a week before further decrease is attempted.

During withdrawal, some patients may experience symptoms of systemically active steroid withdrawal, e.g., joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement of respiratory function. Such patients should be encouraged to continue with beclomethasone dipropionate 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 continue more slowly.

During periods of stress or a severe asthma attack, transfer patients will require supplementary treatment with systemic steroids.

Exacerbations of bronchial asthma which occur during the course of treatment should be treated with a short course of systemic steroid which is gradually tapered as these symptoms subside. There is no evidence that control of bronchial asthma can be achieved by the administration of beclomethasone dipropionate in amounts greater than the recommended dosages. 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 beclomethasone dipropionate.

Availability And Storage: Each depression of the metered dose aerosol valve delivers: beclomethasone dipropionate 250 µg suspended in trichlorofluoromethane and dichlorodifluoromethane. Nonmedicinal ingredients: dichlorodifluoromethane, oleic acid and trichlorofluoromethane. Each unit is housed in a suitable actuator/adaptor. Aluminum canisters fitted with metering valves. Becloforte is available in 200 dose containers.

Caution: Container may explode if heated. Contents under pressure. Do not place in hot water or near radiators, stoves or other sources of heat. Even when empty, do not puncture or incinerate container or store at temperatures over 30°C. Protect from freezing and direct sunlight. As with most inhaled medications in aerosol canisters, the therapeutic effect of this medication may decrease when the canister is cold.

BECLOFORTE® Glaxo Wellcome Beclomethasone Dipropionate Corticosteroid for the Treatment of Bronchial Asthma

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