Beclomethasone dipropionate, USP, the active component of VANCERIL 42 mcg Inhalation Aerosol, is an anti-inflammatory steroid having the chemical name 9-Chloro-11(beta),17,21-trihydroxy-16(beta)-methylpregna-1,4-diene-3,20-dione 17,21-dipropionate.

VANCERIL 42 mcg Inhalation Aerosol is a 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, USP, to trichloromonofluoromethane between 3:1 and 3:2. Each actuation delivers from the mouthpiece a quantity of clathrate equivalent to 42 mcg of beclomethasone dipropionate, USP. The contents of one canister provide at least 200 oral inhalations.

Beclomethasone 17, 21-dipropionate is a diester of beclomethasone, a synthetic corticosteroid which is chemically related to dexamethasone. Beclomethasone differs from dexamethasone only in having a chlorine at the 9-alpha in place of a fluorine and in having a 16(beta)-methyl group instead of a 16 alpha-methyl group. Animal studies show that beclomethasone dipropionate has potent anti-inflammatory activity. When administered systemically to mice, the anti-inflammatory activity was accompanied by other typical features of glucocorticoid action including thymic involution, liver glycogen deposition, and pituitary-adrenal suppression. However, after systemic administration 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 in 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 radioactivity 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 is excreted in the urine as both conjugated and free metabolites of the drug.

The mechanisms responsible for the anti-inflammatory action of beclomethasone dipropionate are unknown. The precise mechanism of the aerosolized drug' action in the lung is also unknown.

INDICATIONS

VANCERIL 42 mcg Inhalation Aerosol is indicated only for patients who required chronic treatment with corticosteroids for control of the symptoms of bronchial asthma. Such patients would include those already receiving systemic corticosteroids, and selected patients who are inadequately controlled on a nonsteroid regimen and in whom steroid therapy has been withheld because of concern over potential adverse effects.

VANCERIL 42 mcg Inhalation Aerosol is NOT indicated:

1. For relief of asthma which can be controlled by bronchodilators and other nonsteroid medications.
2. In patients who require systemic corticosteroid treatment infrequently.
3. In the treatment of nonasthmatic bronchitis.

CONTRAINDICATIONS

VANCERIL 42 mcg 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.

Localized infections with Candida albicans or Aspergillus niger have occurred frequently 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 may require treatment with appropriate antifungal therapy or discontinuance of treatment with VANCERIL 42 mcg Inhalation Aerosol.

VANCERIL 42 mcg Inhalation Aerosol is not to be regarded as a bronchodilator and is not indicated for rapid relief of bronchospasm.

Patients should be instructed to contact their physician immediately when episodes of asthma which are not responsive to bronchodilators occur during the course of treatment with VANCERIL 42 mcg Inhalation Aerosol. During such episodes, patients may require therapy with systemic corticosteroids.

There is no evidence that control of asthma can be achieved by the administration of VANCERIL 42 mcg Inhalation Aerosol in amounts greater than the recommended doses.

Transfer of patients from systemic steroid therapy to VANCERIL 42 mcg Inhalation Aerosol may unmask allergic conditions previously suppressed by the systemic steroid therapy, eg, rhinitis, conjunctivitis, and eczema.

Persons who are on drugs which 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 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.

PRECAUTIONS

During withdrawal from oral steroids, some patients may experience symptoms of systemically active steroid withdrawal, eg, joint and/or muscular pain, lassitude and depression, despite maintenance or even improvement of respiratory function. (See DOSAGE AND ADMINISTRATION for details.)

In responsive patients, beclomethasone dipropionate may permit control of asthmatic symptoms without suppression of HPA function, as discussed below. (See CLINICAL STUDIES .) Since beclomethasone dipropionate is absorbed into the circulation and can be systemically active, the beneficial effects of VANCERIL 42 mcg Inhalation Aerosol in minimizing or preventing HPA dysfunction may be expected only when recommended dosages are not exceeded.

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 lung are unknown. There is also no information about the possible long-term systemic effects of the agent.

The potential effects of VANCERIL 42 mcg Inhalation Aerosol on acute, recurrent, or chronic pulmonary infections, including active or quiescent tuberculosis, are not known. Similarly, the potential effects of long-term administration of the drug on lung or other tissues are unknown.

Pulmonary infiltrates with eosinophilia may occur in patients on VANCERIL 42 mcg Inhalation Aerosol 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.

Use in Pregnancy:   Glucocorticoids are known teratogens in rodent species and beclomethasone dipropionate is no exception.

Teratology studies were done in rats, mice, and rabbits treated with subcutaneous beclomethasone dipropionate. Beclomethasone dipropionate was found to produce fetal resorptions, cleft palate, agnathia, microstomia, absence of tongue, delayed ossification, and partial agenesis of the thymus. Well-controlled trials relating to fetal risk in humans are not available. Glucocorticoids are secreted in human milk. It is not known whether belcomethasone dipropionate would be secreted in human milk but it is safe to assume that it is 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, embryo, or fetus. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for hypoadrenalism.

Information for Patients:   Persons who are on immunosuppressant doses of corticosteroids 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.

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 1600 mcg daily doses of VANCERIL 42 mcg Inhalation Aerosol for 1 month. A few patients on VANCERIL 42 mcg Inhalation Aerosol have complained of hoarseness or dry mouth.

Rare cases of immediate and delayed hypersensitivity reactions, including urticaria, angioedema, rash, and bronchospasm have been reported following the oral and intranasal inhalation of beclomethasone.

DOSAGE AND ADMINISTRATION

Adults:   The usual recommended dosage is two inhalations (84 mcg) given three or four times a day. Alternatively, four inhalations (168 mcg) given twice daily has 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 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 has been shown to be effective in some patients. The maximal daily intake should not exceed ten inhalations, 420 mcg (0.42 mcg), in children 6 to 12 years of age. Insufficient clinical data exist with respect to the administration of VANCERIL 42 mcg Inhalation Aerosol in children below the age of 6.

Rinsing the mouth after inhalation is advised.

Patients receiving bronchodilators by inhalation should be advised to use the bronchodilator before VANCERIL 42 mcg Inhalation Aerosol in order to enhance penetration of beclomethasone dipropionate into the bronchial tree. After use of an aerosol bronchodilator, several minutes should elapse before use of the VANCERIL 42 mcg Inhalation Aerosol to reduce the potential toxicity from the inhaled fluorocarbon propellants in the two aerosols.

Different considerations must be given to the following groups of patients in order to obtain the full therapeutic benefit of VANCERIL 42 mcg Inhalation Aerosol.

Patients Not Receiving Systemic Steroids:   The use of VANCERIL 42 mcg Inhalation Aerosol is straightforward in patients who are inadequately controlled with nonsteroid medications but in whom systemic steroid therapy has been withheld because of concern over potential adverse reactions. In patients who respond to VANCERIL, an improvement in pulmonary function is usually apparent within 1 to 4 weeks after the start of VANCERIL 42 mcg Inhalation Aerosol.

Patients Receiving Systemic Steroids:   In those patients dependent on systemic steroids, transfer to VANCERIL 42 mcg Inhalation Aerosol and subsequent management may be more difficult because of recovery from impaired adrenal function is usually slow. Such suppression has been known to last for up to 12 months. Clinical studies, however, have demonstrated that VANCERIL may be effective in the management of these asthmatic patients and may permit replacement or significant reduction in the dosage of systemic corticosteriods.

The patient' asthma should be reasonably stable before treatment with VANCERIL 42 mcg Inhalation Aerosol is started. Initially, the aerosol should be used concurrently with the patient' usual maintenance dose of systemic steroid. After approximately 1 week, gradual withdrawal of the systemic steroid is started by reducing the daily or alternate daily dose. The next reduction is 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. A slow rate of withdrawal cannot be overemphasized. During withdrawal, some patients may experience symptoms of systemically active steroid withdrawal, eg, joint and/or muscular pain, lassitude and depression, despite maintenance or even improvement of respiratory function. Such patients should be encouraged to continue with the inhaler 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 dose 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 asthma which occur during the course of treatment with VANCERIL 42 mcg Inhalation Aerosol 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 asthma can be achieved by administration of VANCERIL in amounts greater than the recommended doses.

Directions for Use:   Illustrated Patient' Instructions for proper use accompany each package of VANCERIL 42 mcg 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

VANCERIL 42 mcg Inhalation Aerosol 16.8 g canister supplied with an oral adapter and Patient' Instructions; box of one (NDC 0085-0736-04). Institutional Pack for Inpatient Use Only: VANCERIL 42 mcg Inhalation Aerosol 6.7 g canister supplied with an oral adapter and Patient' Instructions; box of one (NDC 0085-0738-01).

Store between 15° and 30°C (59° and 86°F). Protect from moisture and unusual temperature fluctuations. Shake well before using. Failure to use the product within this temperature range may result in improper dosing.

Note :   The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFCs).

WARNING :  Contains dichlorodifluoromethane (CFC-11) and trichloromonofluoromethane (CFC-12), substances which harm public health and the environment by destroying ozone in the upper atmosphere.

A notice similar to the above WARNING has been placed in the "Patient' Instructions" portion of this package insert pursuant to EPA regulations.

ANIMAL PHARMACOLOGY AND TOXICOLOGY

Studies in a number of animal species including rats, rabbits, and dogs have shown no unusual toxicity during acute experiments. However, the effects of beclomethasone dipropionate in producing signs of glucocorticoid excess during chronic administration by various routes were dose related.

CLINICAL STUDIES

The effects of beclomethasone dipropionate on hypothalamic-pituitary-adrenal (HPA) function have been evaluated in adult volunteers. There was no suppression of early morning plasma cortisol concentrations when beclomethasone dipropionate was administered at a dose of 1000 mcg/day for 1 month as an aerosol or for 3 days by intramuscular injection. However, partial suppression of plasma cortisol concentration was observed when beclomethasone dipropionate was administered at doses of 2000 mcg/day either intramuscularly or 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 administration of 400, 800, or 1200 mcg of beclomethasone dipropionate for 28 days. After daily administration of 1600 mcg each day for 28 days, there was a slight reduction in basal cortisol concentrations and a statistically significant (p <.01) reduction in plasma cortisol responses to tetracosactrin stimulation. The effects of a more prolonged period of beclomethasone dipropionate administration on HPA function have not been evaluated. However, a number of investigators have noted that when systemic corticosteroid therapy in asthmatic subjects can be replaced with recommended doses of beclomethasone dipropionate, there is gradual recovery of endogenous cortisol concentrations to the normal range. There is still no documented evidence of recovery from other adverse systemic corticosteroid-induced reactions during prolonged therapy of patients with beclomethasone dipropionate.

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

The early clinical experience has revealed several new problems which may be associated with the use of beclomethasone dipropionate by inhalation for treatment of patients with bronchial asthma:

1. There is a risk of adrenal insufficiency when patients are transferred from systemic corticosteroids to aerosol beclomethasone dipropionate. Although the aerosol may provide adequate control of asthma during the transfer period, it does not provide the systemic steroid which is needed during acute stress situations. Deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to aerosol beclomethasone dipropionate. (See .)
2. Transfer of patients from systemic steroid therapy to beclomethasone dipropionate aerosol may unmask allergic conditions which were previously controlled by the systemic steroid therapy, eg, rhinitis, conjunctivitis, and eczema.
3. Localized infections with Candida albicans or Aspergillus niger have occurred frequently in the mouth and pharynx and occasionally in the larynx. It has been reported that up to 75% of the patients who receive prolonged treatment with beclomethasone dipropionate have positive oral cultures for Candida albicans . The incidence of clinically apparent infection is considerably lower but may require therapy with appropriate antifungal agents or discontinuation of treatment with beclomethasone dipropionate aerosol.

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 lung are unknown. There is also no information about the possible long-term systemic effects of the agent. The possible relevance of the data in animal studies to results in human subjects cannot be evaluated.

Schering Corporation

Kenilworth, NJ 07033 USA

Rev. 4/97                                     20108908

Copyright © 1973, 1995, 1996, 1997, Schering Corporation.

All rights reserved.

VANCERIL® 42 mcg

(beclomethasone dipropionate, 42 mcg) Inhalation Aerosol

For Oral Inhalation Only

PATIENT' INSTRUCTIONS

It is important that you read these instructions before using your VANCERIL 42 mcg Inhalation Aerosol. Correct and regular use of the inhaler will prevent or lessen the severity of asthma attacks.

1. SHAKE THE INHALER WELL and remove the plastic cap (see Figure 1).
   
2. As with all aerosol medications, it is recommended to "test spray" into the air before using for the first time and in cases where the aerosol has not been used for a prolonged period of time.
3. BREATHE OUT AS FULLY AS YOU COMFORTABLY CAN. Hold the inhaler in the upright position and put the mouthpiece into your mouth (see Figure 2). Close your lips around the mouthpiece, keeping your tongue below it.
   
4. WHILE BREATHING IN DEEPLY, PRESS DOWN ON THE CAN WITH YOUR FIRST FINGER. When you have finished breathing in, hold your breath as long as you comfortably can.
5. TAKE YOUR FINGER OFF THE CAN and remove the inhaler from your mouth. Breathe out gently.
6. If your physician has told you to take more than one inhalation per treatment, wait 1 minute between puffs. Shake the inhaler well and repeat steps 3 through 5.
7. It is recommended that you rinse your mouth thoroughly with water, gargle, or drink water after inhalation(s), whenever possible.
8. CLEAN YOUR INHALER AT LEAST ONCE A DAY. Remove the can and rinse the plastic case and cap in warm running water. Dry the case and cap and gently replace the metal canister into the case with a twisting motion. Put the cap on the mouthpiece.
9. DISCARD THE CANISTER AFTER the date calculated by your physician or pharmacist. The correct amount of medication in each inhalation cannot be assured after a specified number of inhalations even though the canister is not completely empty. Before the discard date you should consult your physician to determine whether a refill is needed. Just as you should not take extra doses without consulting your physician, you also should not stop VANCERIL without consulting your physician.

IMPORTANT:   VANCERIL 42 mcg Inhalation Aerosol is preventive therapy for asthma and must be used regularly and at the times your physician has prescribed. DO NOT CONFUSE VANCERIL 42 mcg Inhalation Aerosol WITH OTHER ASTHMA MEDICATION. VANCERIL 42 mcg Inhalation Aerosol WILL NOT PROVIDE IMMEDIATE RELIEF IF YOU ARE HAVING AN ATTACK. Your physician will decide whether other medication is needed should you require immediate relief. If you also use another medicine by inhalation, you should consult your physician for instructions on when to use it in relation to using VANCERIL. If this is the first time you will be using VANCERIL 42 mcg Inhalation Aerosol, it may take from 1 to 4 weeks before you feel the full benefits.

Dosage  Use only as directed by your physician.

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.

Store between 15° and 30°C (59° and 86°F). Protect from moisture and unusual temperature fluctuations. Shake well before using. Failure to use the product within this temperature range may result in improper dosing.

Note:  The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFCs).

This product contains dichlorodifluromethane (CFC-11) and trichloromonofluoromethane (CFC-12), substances which harm the environment by destroying ozone in the upper atmosphere.

Your physician has determined that this product is likely to help your personal health. USE THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE BY YOUR PHYSICIAN. If you have any questions about alternatives, consult with your physician.

Schering Corporation

Kenilworth, NJ 07033 USA

Copyright © 1973, 1995, 1996, 1997,

Schering Corporation.

All rights reserved.                  Rev. 4/97