Beclomethasone dipropionate, USP, the active component of BECLOVENT Inhalation Aerosol, is an anti-inflammatory corticosteroid having the chemical name 9-chloro-11(beta),17,21-trihydroxy-16(beta)-methylpregna-1,4-diene-3,20-dione 17,21-dipropionate.

Beclomethasone 17,21-dipropionate is a diester of beclomethasone, a synthetic halogenated corticosteroid. Beclomethasone dipropionate is a white to creamy-white, odorless powder with a molecular formula of C 28 H 37 ClO 7 and a molecular weight of 521.05. It is very slightly soluble in water, very soluble in chloroform, and freely soluble in acetone and in alcohol.

BECLOVENT Inhalation Aerosol is a pressurized metered-dose aerosol unit containing a microcrystalline suspension of beclomethasone dipropionate-trichloromonofluoromethane clathrate in a mixture of propellants (trichloromonofluoromethane and dichlorodifluoromethane) with oleic acid. Each canister contains beclomethasone dipropionate-trichloromonofluoromethane clathrate having a molecular proportion of beclomethasone dipropionate to trichloromonofluoromethane between 3:1 and 3:2. Each actuation delivers a quantity of clathrate equivalent to 42 mcg of beclomethasone dipropionate, USP from the mouthpiece and 50 mcg from the valve. The contents of one 6.7-g canister provide 80 oral inhalations, and the contents of one 16.8-g canister provide 200 oral inhalations.

Animal studies show that beclomethasone dipropionate has potent anti-inflammatory activity. When beclomethasone dipropionate was administered systemically to mice, the anti-inflammatory activity was accompanied by other features typical of glucocorticoid action, including thymic involution, liver glycogen deposition, and pituitary-adrenal suppression. After systemic administration of beclomethasone dipropionate to rats, the anti-inflammatory action was associated with little or no effect on other tests of glucocorticoid activity.

Beclomethasone dipropionate is sparingly soluble and is poorly mobilized from subcutaneous or intramuscular injection sites. However, systemic absorption occurs after all routes of administration. When given to animals in the form of an aerosolized suspension of the trichloromonofluoromethane clathrate, the drug is deposited in the mouth and nasal passages, the trachea and principal bronchi, and the lung; a considerable portion of the drug is also swallowed. Absorption occurs rapidly from all respiratory and gastrointestinal tissues, as indicated by the rapid clearance of radioactively labeled drug from local tissues and appearance of tracer in the circulation. There is no evidence of tissue storage of beclomethasone dipropionate or its metabolites. Lung slices can metabolize beclomethasone dipropionate rapidly to beclomethasone 17-monopropionate and more slowly to free beclomethasone (which has very weak anti-inflammatory activity). However, irrespective of the route of administration (injection, oral, or aerosol), the principal route of excretion of the drug and its metabolites is the feces. Less than 10% of the drug and its metabolites is excreted in the urine. In humans, 12% to 15% of an orally administered dose of beclomethasone dipropionate was excreted in the urine as both conjugated and free metabolites of the drug.

The precise mechanisms of glucocorticoid action in asthma are unknown. Inflammation is recognized as an important component in the pathogenesis of asthma. Glucocorticoids have been shown to inhibit multiple cell types (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils) and mediator production or secretion (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in the asthmatic response. These anti-inflammatory actions of glucocorticoids may contribute to their efficacy in asthma.

Clinical Trials:   The effects of beclomethasone dipropionate on HPA function have been evaluated in adult volunteers. There was no suppression of early morning plasma cortisol concentrations when beclomethasone dipropionate was administered in a dose of 840 mcg/day for 1 month as an aerosol or 1000 mcg/day for 3 days by intramuscular injection. However, partial suppression of plasma cortisol concentration was observed when beclomethasone dipropionate was administered in doses of 2000 mcg/day intramuscularly or 1680 mcg/day by aerosol. Immediate suppression of plasma cortisol concentrations was observed after single doses of 4000 mcg of beclomethasone dipropionate.

In one study the effects of beclomethasone dipropionate on HPA function were examined in patients with asthma. There was no change in basal early morning plasma cortisol concentrations or in the cortisol responses to tetracosactrin (ACTH 1:24) stimulation after daily aerosol administration of 336, 672, or 1008 mcg of beclomethasone dipropionate for 28 days. After daily aerosol administration of 1344 mcg for 28 days, there was slight reduction in basal cortisol concentrations and a statistically significant ( P <.01) reduction in plasma cortisol responses to tetracosactrin stimulation. Following 52 weeks of aerosol treatment with 840 mcg of beclomethasone dipropionate daily, 7/115 (6%) of patients exhibited a plasma cortisol measurement below the lower limit of normal (150 nmol -1 ).

Clinical experience has shown that some patients with asthma who require corticosteroid therapy for control of symptoms can be partially or completely withdrawn from systemic corticosteroids if therapy with beclomethasone dipropionate aerosol is substituted. Beclomethasone dipropionate aerosol is not effective for all patients with asthma or at all stages of the disease in a given patient.

INDICATIONS

BECLOVENT Inhalation Aerosol is indicated in the maintenance treatment of asthma as prophylactic therapy. BECLOVENT Inhalation Aerosol is also indicated for asthma patients who require systemic corticosteroid administration, where adding BECLOVENT Inhalation Aerosol may reduce or eliminate the need for the systemic corticosteroids.

BECLOVENT Inhalation Aerosol is NOT indicated for the relief of acute bronchospasm.

CONTRAINDICATIONS

BECLOVENT Inhalation Aerosol is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.

Hypersensitivity to any of the ingredients of this preparation contraindicates its use.

Particular care is needed in patients who are transferred from systemically active corticosteroids to BECLOVENT Inhalation Aerosol 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 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 BECLOVENT Inhalation Aerosol may provide control of asthmatic symptoms during these episodes, it does NOT provide the systemic steroid that 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 doses) 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 resting 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.

Localized infections with Candida albicans or Aspergillus niger have occurred in the mouth and pharynx and occasionally in the larynx. Positive cultures for oral Candida may be present in up to 75% of patients. Although the frequency of clinically apparent infection is considerably lower, these infections can develop with any inhaled corticosteroid and may require treatment with appropriate antifungal therapy or discontinuation of treatment with BECLOVENT Inhalation Aerosol.

BECLOVENT Inhalation Aerosol is not a bronchodilator and is not indicated for rapid relief of bronchospasm.

Patients should be instructed to contact their physicians immediately when episodes of asthma that are not responsive to bronchodilators occur during the course of treatment with BECLOVENT Inhalation Aerosol. During such episodes, patients may require therapy with systemic corticosteroids.

Transfer of patients from systemic corticosteroid therapy to BECLOVENT Inhalation Aerosol may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, and eczema.

Persons 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 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 pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

Avoid spraying in eyes.

PRECAUTIONS

During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement of respiratory function (see DOSAGE AND ADMINISTRATION ).

In responsive patients, beclomethasone dipropionate may permit control of asthmatic symptoms without suppression of HPA function, as discussed above (see ). Since beclomethasone dipropionate is absorbed into the circulation and can be systemically active, the beneficial effects of BECLOVENT Inhalation Aerosol in minimizing or preventing HPA dysfunction may be expected only when recommended dosages are not exceeded.

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. Therefore, if such changes occur, BECLOVENT Inhalation Aerosol should be discontinued slowly, consistent with accepted procedures for discontinuing oral steroids.

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 an adolescent' growth appears slowed.

The long-term local and systemic effects of BECLOVENT Inhalation Aerosol in human subjects are still not fully known. In particular, the effects resulting from chronic use of BECLOVENT Inhalation Aerosol on developmental or immunologic processes in the mouth, pharynx, trachea, and lung are unknown.

Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial, parasitic, or viral infections; or ocular herpes simplex.

Pulmonary infiltrates with eosinophilia may occur in patients on BECLOVENT Inhalation Aerosol therapy. Although it is possible that in some patients this state may become manifest because of systemic corticosteroid withdrawal when inhalational corticosteroids are administered, a causative role for beclomethasone dipropionate and/or its vehicle cannot be ruled out.

Information for Patients:   Patients being treated with BECLOVENT Inhalation Aerosol should receive the following information and instructions. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

Patients should use BECLOVENT Inhalation Aerosol at regular intervals as directed. Results of clinical trials indicated significant improvement may occur within the first day or two of treatment; however, the full benefit may not be achieved until treatment has been administered 1 or 2 weeks or longer. The patient should not increase the prescribed dosage but should contact the physician if symptoms do not improve or if the condition worsens.

Patients should be advised that BECLOVENT Inhalation Aerosol is not intended for use in the treatment of acute asthma. Patients should be made aware of the prophylactic nature of therapy with inhaled beclomethasone dipropionate and that it should be taken regularly even when they are asymptomatic. Patients should be instructed to contact their physicians immediately if there is any deterioration of their asthma.

BECLOVENT Inhalation Aerosol should not be stopped abruptly. If discontinuing use of BECLOVENT Inhalation Aerosol is necessary, the patient' physician should be contacted immediately.

Each patient should be advised to rinse his/her mouth each time after using BECLOVENT Inhalation Aerosol.

Patients should be warned to avoid exposure to chickenpox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay.

Carcinogenesis, Mutagenesis, Impairment of Fertility:   The carcinogenicity of beclomethasone dipropionate was evaluated in rats that were exposed for a total of 95 weeks, 13 weeks at inhalation doses up to 0.4 mg/kg and the remaining 82 weeks at combined oral and inhalation doses up to 2.4 mg/kg. There was no evidence of carcinogenicity in this study at the highest dose, approximately 20 or 36 times the maximum recommended daily inhalation dose in adults and children, respectively, on a mg/m 2 basis

Beclomethasone dipropionate did not induce gene mutation in bacterial cells or mammalian Chinese Hamster ovary (CHO) cells in vitro. No significant clastogenic effect was seen in cultured CHO cells in vitro or in the mouse micronucleus test in vivo.

In rats, beclomethasone dipropionate caused decreased conception rates at an oral dose of 16 mg/kg (approximately 130 times the maximum recommended daily inhalation dose in adults on a mg/m 2 basis). Inhibition of the estrous cycle in dogs was observed following oral dosing at 0.5 mg/kg (approximately 15 times the maximum recommended daily inhalation dose in adults on a mg/m 2 basis). No inhibition of the estrous cycle in dogs was seen following 12 months' exposure at an estimated daily inhalation dose of 0.33 mg/kg (approximately 9 times the maximum recommended daily inhalation dose in adults on a mg/m 2 basis

Pregnancy: Teratogenic Effects:   Pregnancy Category C. Like other corticosteroids, beclomethasone dipropionate was teratogenic and embryocidal in the mouse and rabbit at a subcutaneous dose of 0.1 mg/kg in mice or 0.025 mg/kg in rabbits (approximately 1/2 the maximum recommended daily inhalation dose in adults on a mg/m 2 basis). No teratogenicity or embryocidal effects were seen in rats when exposed to an inhalation dose of 0.1 mg/kg plus oral doses of up to 10 mg/kg per day for a combined dose of 10.1 mg/kg (approximately 80 times the maximum recommended daily inhalation dose in adults on a mg/m 2 basis). There are no adequate and well-controlled studies in pregnant women. BECLOVENT Inhalation Aerosol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers:   Corticosteroids are secreted in human milk. Because of the potential for serious adverse reactions in nursing infants for BECLOVENT Inhalation Aerosol, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use:   The safety and effectiveness of BECLOVENT Inhalation Aerosol have been established in children aged 6 years and above. The safety and effectiveness of BECLOVENT Inhalation Aerosol in children below 6 years of age have not been established. Corticosteroids have been shown to cause a reduction in growth velocity in children and teenagers with extended use. If a child or teenager on any corticosteroid appears to have growth suppression, the possibility that they are particularly sensitive to this effect of corticosteroids should be considered (see PRECAUTIONS ).

ADVERSE REACTIONS

Deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to aerosol beclomethasone dipropionate (see ) .

Suppression of HPA function (reduction of early morning plasma cortisol levels) has been reported in adult patients who received 1344-mcg daily doses of BECLOVENT Inhalation Aerosol for 1 month. A few patients on BECLOVENT Inhalation Aerosol have complained of hoarseness or dry mouth.

In addition, the following adverse events have been reported spontaneously during worldwide postmarketing surveillance. Therefore, the frequency of events and causality cannot be reliably determined. The adverse events reported in association with BECLOVENT Inhalation Aerosol include:

General:   Immediate and delayed hypersensitivity reactions including anaphylactic/anaphylactoid reactions, angioedema, bronchospasm, rash, urticaria.

Ear, Nose, and Throat:   Dryness and irritation of the nose, throat, and mouth; hoarseness; localized infections with Candida or Aspergillus ; unpleasant taste and smell; loss of taste and smell.

Endocrine and Metabolic:   Cushingoid features, growth velocity reduction in children/adolescents, weight gain.

Eye:   Cataracts, glaucoma, increased intraocular pressure.

Gastrointestinal:   Nausea, vomiting.

Nervous:   Dizziness, headache, lightheadedness.

Psychiatry   Agitation, depression, mental disturbances.

Respiratory   Paradoxical bronchospasm, wheezing.

Skin   Acneiform lesions, atrophy, bruising, pruritus, purpura, striae.

OVERDOSAGE

For maximum doses studied in humans, see the Clinical Trials subsection. Chronic overdosage may result in signs/symptoms of hypercorticism (see PRECAUTIONS ). No deaths occurred when beclomethasone dipropionate was given as single oral doses of 3000 mg/kg to mice and 2000 mg/kg to rats (approximately 12 000 and 16 000 times, respectively, the maximum recommended human daily inhalation dose on a mg/m 2 basis).

DOSAGE AND ADMINISTRATION

BECLOVENT Inhalation Aerosol should be test sprayed into the air before using for the first time and in cases where the product has not been used for a prolonged period of time.

Adults and Children 12 Years of Age and Older:   The usual recommended dosage is two inhalations (84 mcg) given three or four times a day. Alternatively, four inhalations (168 mcg) given twice daily have been shown to be effective in some patients. In patients with severe asthma, it is advisable to start with 12 to 16 inhalations a day (504 to 672 mcg) and adjust the dosage downward according to the response of the patient. The maximal daily intake should not exceed 20 inhalations, 840 mcg (0.84 mg), in adults .

Children 6 to 12 Years of Age:   The usual recommended dosage is one or two inhalations (42 to 84 mcg) given three or four times a day according to the response of the patient. Alternatively, four inhalations (168 mcg) given twice daily have been shown to be effective in some patients. The maximal daily intake should not exceed 10 inhalations, 420 mcg (0.42 mg), in children 6 to 12 years of age . Insufficient clinical data exist with respect to the administration of BECLOVENT Inhalation Aerosol in children below the age of 6.

Rinsing the mouth after inhalation is advised.

Different considerations must be given to the following groups of patients in order to obtain the full therapeutic benefit of BECLOVENT Inhalation Aerosol .

Patients Not Receiving Systemic Corticosteroids:   Patients who require maintenance therapy of their asthma may benefit from treatment with BECLOVENT Inhalation Aerosol at the doses recommended above. In patients who respond to BECLOVENT Inhalation Aerosol, improvement in pulmonary function is usually apparent within 1 to 4 weeks after the start of therapy. Once the desired effect is achieved, consideration should be given to tapering to the lowest effective dose.

Patients Maintained on Systemic Corticosteroids:   Clinical studies have shown that BECLOVENT Inhalation Aerosol may be effective in the management of asthmatics dependent or maintained on systemic corticosteroids and may permit replacement or significant reduction in the dosage of systemic corticosteroids.

The patient' asthma should be reasonably stable before treatment with BECLOVENT Inhalation Aerosol is started. Initially, BECLOVENT Inhalation Aerosol should be used concurrently with the patient' usual maintenance dose of systemic corticosteroid. After approximately 1 week, gradual withdrawal of the systemic corticosteroid is started by reducing the daily or alternate-daily dose. Reductions may be made after an interval of 1 or 2 weeks, depending on the response of the patient. Generally, these decrements should not exceed 2.5 mg of prednisone or its equivalent. During withdrawal, some patients may experience symptoms of systemic corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement in pulmonary function. Such patients should be encouraged to continue with the inhaler but should be monitored for objective signs of adrenal insufficiency. If evidence of adrenal insufficiency occurs, the systemic corticosteroid doses should be increased temporarily and thereafter withdrawal should continue more slowly.

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

Directions for Use:   Illustrated Patient' Instructions for Use accompany each package of BECLOVENT Inhalation Aerosol.

CONTENTS UNDER PRESSURE:   Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw container into fire or incinerator. Keep out of reach of children.

HOW SUPPLIED

BECLOVENT Inhalation Aerosol is supplied in a 6.7-g canister containing 80 metered inhalations with oral adapter and patient' instructions (NDC 0173-0469-00) and in a 16.8-g canister containing 200 metered inhalations with oral adapter and patient' instructions (NDC 0173-0312-88). Also available, BECLOVENT Inhalation Aerosol Refill 16.8-g canister only with patient' instructions (NDC 0173-0312-98). Each actuation delivers a quantity of clathrate equivalent to 42 mcg of beclomethasone dipropionate, USP from the mouthpiece and 50 mcg from the valve.

The BECLOVENT Inhalation Aerosol canister should only be used with the tan BECLOVENT Inhalation Aerosol mouthpiece, and this mouthpiece should not be used with any other inhalation product. A dark brown cap fits over the mouthpiece when not in use.

The correct amount of medication in each inhalation cannot be assured after 80 inhalations from the 6.7-g canister or 200 inhalations from the 16.8-g canister even though the canister is not completely empty. The canister should be discarded when the labeled number of actuations has been used.

Store between 2° and 30°C (36° and 86°F). As with most inhaled medications in aerosol canisters, the therapeutic effect of this medication may decrease when the canister is cold. For optimal results, the canister should be at room temperature before use. Shake well before using.

Glaxo Wellcome Inc., Research Triangle Park, NC 27709

December 1997/RL-536

PRODUCT PHOTO(S):

NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual or relative size.

The product samples shown here have been supplied by the manufacturer and reproduced in full color by PDR as a quick-reference identification aid. While every effort has been made to assure accurate reproduction, please remember that any visual identification should be considered preliminary. In cases of poisoning or suspected overdosage, the drug' identity should be verified by chemical analysis.

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