Beclomethasone dipropionate, USP, the active component of VANCENASE POCKETHALER (beclomethasone dipropionate nasal 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, and the following formula:

Beclomethasone dipropionate is a white to creamy-white, odorless powder with a molecular weight of 521.25. It is very slightly soluble in water, very soluble in chloroform, and freely soluble in acetone and in alcohol.

VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol) is a metered-dose aerosol unit containing a microcrystalline suspension of beclomethasonedipropionate-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 trichloromonofluoroethane between 3:1 and 3:2. Each actuation delivers from the nasal adapter a quantity of clathrate equivalent to 42 mcg of beclomethasone dipropionate, USP. The contents of one canister provide at least 200 metered doses.

Beclomethasone 17,21-dipropionate is a diester of beclomethasone, a synthetic halogenated corticosteroid. Animal studies showed that beclomethasone dipropionate has potent glucocorticoid and weak mineralocorticoid activity. The mechanisms for the anti-inflammatory action of beclomethasone dipropionate are unknown. The precise mechanism of the aerosolized drug' action in the nose is also unknown. Biopsies of nasal mucosa obtained during clinical studies showed no histopathologic changes when beclomethasone dipropionate was administered intranasally.

The effects of beclomethasone dipropionate on hypothalamic-pituitary-adrenal (HPA) function have been evaluated in adult volunteers by other routes of administration. Studies are currently being undertaken with beclomethasone dipropionate by the intranasal route, which may demonstrate that there is more or that there is less absorption by this route of administration. There was no suppression of early morning plasma cortisol concentrations when beclomethasone dipropionate was administered in a dose of 1000 mcg/day for 1 month as an oral aerosol or 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 either by oral aerosol or intramuscularly. Immediate suppression of plasma cortisol concentrations was observed after single doses of 4000 mcg of beclomethasone dipropionate. Suppression of HPA function (reduction of early morning plasma cortisol levels) has been reported in adult patients who received 1600 mcg daily doses of oral beclomethasone dipropionate for 1 month. In clinical studies using beclomethasone dipropionate intranasally, there was no evidence of adrenal insufficiency.

Beclomethasone dipropionate is sparingly soluble. When given by nasal inhalation in the form of an aqueous or aerosolized suspension, the drug is deposited primarily in the nasal passages. A portion of the drug is swallowed. Absorption occurs rapidly from all respiratory and gastrointestinal tissues. There is no evidence of tissue storage of beclomethasone dipropionate or its metabolites. In vitro studies have shown that tissue other than the liver (lung slices) can rapidly metabolize beclomethasone dipropionate to beclomethasone 17-monopropionate and more slowly to free beclomethasone (which has very weak anti-inflammatory activity). However, irrespective of the route of entry, the principal route of excretion of the drug and its metabolites is the feces. 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.

Studies have shown that the degree of binding to plasma proteins is 87%.

VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol) is indicated for the relief of the symptoms of seasonal or perennial rhinitis in those cases poorly responsive to conventional treatment.

VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol) is also indicated for the prevention of recurrence of nasal polyps following surgical removal.

Clinical studies in seasonal and perennial rhinitis have shown that improvement is usually apparent within a few days. However, symptomatic relief may not occur in some patients for as long as 2 weeks. Although systemic effects are minimal at recommended doses, VANCENASE treatment should not be continued beyond 3 weeks in the absence of significant symptomatic improvement. VANCENASE treatment should not be used in the presence of untreated, localized infection involving the nasal mucosa.

Clinical studies have shown that treatment of the symptoms associated with nasal polyps may have to be continued for several weeks or more before a therapeutic result can be fully assessed. Recurrence of symptoms due to polyps can occur after stopping treatment, depending on the severity of the disease.

CONTRAINDICATIONS

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

The replacement of a systemic corticosteroid with VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol) can be accompanied by signs of adrenal insufficiency.

Careful attention must be given when patients, previously treated for prolonged periods with systemic corticosteroids, are transferred to VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol). This is particularly important in those patients who have associated asthma or other clinical conditions, where too rapid a decrease in systemic corticosteroids may cause a severe exacerbation of their symptoms.

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

If recommended doses of intranasal beclomethasone are exceeded or if individuals are particularly sensitive or predisposed by virtue of recent systemic steroid therapy, symptoms of hypercorticism may occur, including very rare cases of menstrual irregularities, acneiform lesions, and cushingoid features. If such changes occur, VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol) should be discontinued slowly, consistent with accepted procedures for disontinuing oral steroid therapy.

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 pediatric patients or adults on corticosteroids. In such pediatric patients or adults who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route, and duration of corticoteroid 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

General: During withdrawal from oral steroids, some patients may experience symptoms of withdrawal, eg, joint and/or muscular pain, lassitude, and depression.

Extremely rare instances of nasal septum perforation and increased intraocular pressure have been reported following the intranasal application of aerosolized corticosteroids.

In clinical studies with beclomethasone dipropionate administered intranasally, the development of localized infections of the nose and pharynx with Candida albicans has occurred only rarely. When such an infection develops, it may require treatment with appropriate local therapy or discontinuance of treatment with VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol).

Beclomethasone dipropionate is absorbed into the circulation. Use of excessive doses of VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol) may suppress HPA function.

VANCENASE treatment should be used with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract, or in untreated fungal, bacterial, systemic viral infections, or ocular herpes simplex.

For VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol) to be effective in the treatment of nasal polyps, the aerosol must be able to enter the nose. Therefore, treatment of nasal polyps with VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol) should be considered adjunctive therapy to surgical removal and/or the use of other medications which will permit effective penetration of the VANCENASE product into the nose. Nasal polyps may recur after any form of treatment.

As with any long-term treatment, patients using VANCENASE treatment over several months or longer should be examined periodically for possible changes in the nasal mucosa.

Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal septum ulcers, nasal surgery, or trauma should not use a nasal corticosteroid until healing has occurred.

Nasal and inhaled corticosteroids have been associated with the development of glaucoma and/or cataracts. Therefore, close follow-up is warranted in patients with a change in vision and with a history of glaucoma and/or cataracts.

Although systemic effects have been minimal with recommended doses, this potential increases with excessive doses. Therefore, larger than recommended doses should be avoided.

Information for Patients: Patients should use VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol) at regular intervals since its effectiveness depends on its regular use. The patient should take the medication as directed. It is not acutely effective and the prescribed dosage should not be increased. Instead, nasal vasoconstrictors or oral antihistamines may be needed until the effects of VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol) are fully manifested. One to 2 weeks may pass before full relief is obtained. The patient should contact the doctor if symptoms do not improve, if the condition worsens, or if sneezing or nasal irritation occurs. For the proper use of this unit and to attain maximum improvement, the patient should read and follow the accompanying PATIENT' INSTRUCTIONS carefully.

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Treatment of rats for a total of 95 weeks, 13 weeks by inhalation and 82 weeks by the oral route, resulted in no evidence of carcinogenic activity. Mutagenic studies have not been performed.

Impairment of fertility, as evidenced by inhibition of the estrous cycle in dogs, was observed following treatment by the oral route. No inhibition of the estrous cycle in dogs was seen following treatment with beclomethasone dipropionate by the inhalation route.

Pregnancy Category C: Like other corticoids, parenteral (subcutaneous) beclomethasone dipropionate has been shown to be teratogenic and embryocidal in the mouse and rabbit when given in doses approximately ten times the human dose. In these studies, beclomethasone was found to produce fetal resorption, cleft palate, agnathia, microstomia, absence of tongue, delayed ossification, and agenesis of the thymus. No teratogenic or embryocidal effects have been seen in the rat when beclomethasone dipropionate was administered by inhalation at ten times the human dose or orally at 1000 times the human dose. There are no adequate and well-controlled studies in pregnant women. Beclomethasone dipropionate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully observed.

Nursing Mothers: It is not known whether beclomethasone dipropionate is excreted in human milk. Because other corticosteroids are excreted in human milk, caution should be exercised when VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol) is administered to nursing women.

Pediatric Use: Safety and effectiveness in pediatric patients below the age of 6 years have not been established.

ADVERSE REACTIONS

In general, side effects in clinical studies have been primarily associated with the nasal mucous membranes. Adverse reactions reported in controlled clinical trials and in long-term open studies in patients treated with VANCENASE Nasal Inhaler are described below.

Sensations of irritation and burning in the nose (11 per 100 patients) following the use of VANCENASE Nasal Inhaler have been reported. Also, occasional sneezing attacks (10 per 100 patients) have occurred immediately following the use of the intranasal inhaler. This symptom may be more common in children.

Rhinorrhea may occur occasionally (1 per 100 patients).

Localized infections of the nose and pharynx with Candida albicans have occurred rarely. (See PRECAUTIONS .)

Transient episodes of epistaxis or bloody discharge from the nose have been reported in 2 per 100 patients.

Ulceration of the nasal mucosa has been reported rarely.

Extremely rare instances of nasal septum perforation have been reported following the intranasal application of aerosolized corticosteroids. 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.

Increased intraocular pressure has been reported rarely. (See PRECAUTIONS .)

Systemic corticosteroid side effects were not reported during controlled clinical trials. If recommended doses are exceeded, however, or if individuals are particularly sensitive, symptoms of hypercorticism, ie, Cushing' syndrome could occur.

DOSAGE AND ADMINISTRATION

Adults and Pediatric Patients 12 Years of Age and Over: The usual dosage is one inhalation (42 mcg) in each nostril two to four times a day (total dose 168-336 mcg/day). Patients can often be maintained on a maximum dose of one inhalation in each nostril three times a day (252 mcg/day).

Pediatric Patients 6 to 12 Years of Age: The usual dosage is one inhalation in each nostril three times a day (252 mcg/day). VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol) is not recommended for pediatric patients below 6 years of age since safety and efficacy studies have not been conducted in this age group.

In patients who respond to VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol), an improvement of the symptoms of seasonal or perennial rhinitis usually becomes apparent within a few days after the start of VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol) therapy. However, symptomatic relief may not occur in some patients for as long as 2 weeks. VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol) should not be continued beyond 3 weeks in the absence of significant symptomatic improvement.

The therapeutic effects of corticosteroids, unlike those of decongestants, on seasonal or perennial rhinitis or on nasal polyps are not immediate. This should be explained to the patient in advance in order to ensure cooperation and continuation of treatment with the prescribed dosage regimen.

VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol) is not recommended for pediatric patients below 6 years of age.

In the presence of excessive nasal mucus secretion or edema of the nasal mucosa, the drug may fail to reach the site of intended action. In such cases it is advisable to use a nasal vasoconstrictor during the first 2 to 3 days of VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol) therapy.

Directions for Use: Illustrated PATIENT' INSTRUCTIONS for proper use accompany each package of VANCENASE POCKETHALER (beclomethasone dipropionate nasal 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.

OVERDOSAGE

When used at excessive doses, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol) should be discontinued slowly consistent with accepted procedures for discontinuing oral steroid therapy.

The oral LD ₅₀ of beclomethasone dipropionate is greater than 1 g/kg in rodents. One canister of VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol) contains 8.4 mg of beclomethasone dipropionate; therefore acute overdosage is unlikely.

HOW SUPPLIED

VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol), 7 g canister; box of one. Supplied with nasal adapter and PATIENT' INSTRUCTIONS (NDC 0085-0649-02).

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-12) and trichloromonofluoromethane (CFC-11), 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 for Use portion of this package insert pursuant to EPA regulations.

Schering Corporation

Kenilworth, NJ 07033 USA

Rev. 10/99 19529649

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.

VANCENASE® POCKETHALER®

(beclomethasone dipropionate

nasal aerosol)

PATIENT' INSTRUCTIONS FOR USE

SHAKE WELL BEFORE USE

Read complete instructions carefully and use only as directed by your physician.

Before using your VANCENASE® POCKETHALER® (beclomethasone dipropionate nasal aerosol), read complete instructions carefully.

Gently blow your nose to clear the nostrils.
SHAKE THE INHALER WELL immediately before each use (Figure 1).
Remove the cap to uncover the plastic nasal piece.
Hold the inhaler as shown in Figure 2.
Tilt the head back. Carefully insert the opening of the plastic nasal piece into one nostril and close the other nostril with one finger (Figure 3).
While gently breathing in through the nostril, press the canister down firmly between finger and thumb to release the medication (Figure 3).
Now breathe out through the mouth (Figure 4).
SHAKE THE INHALER AGAIN and then repeat steps 4 through 7 in the other nostril.
Replace the cap.

Cleaning Remove the metal canister from the plastic nasal inhaler unit. Remove the maroon protective cap. Rinse the plastic nasal inhaler and cap in warm running water once a day. Dry thoroughly. Replace the metal canister into the nasal inhaler unit. Replace the maroon protective cap.

CAUTION: VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol) is not intended to give immediate relief of your nasal symptoms. Improvement with VANCENASE POCKETHALER (beclomethasone dipropionate nasal aerosol) may take a few days to develop, and it is important that you use it regularly at the times recommended 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.

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 dichlorodifluoromethane (CFC-12) and trichloromonofluoromethane (CFC-11), 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.