Beclomethasone dipropionate, USP, the active component of BECONASE 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.
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.
BECONASE 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 to trichloromonofluoromethane between 3:1 and 3:2. Each actuation delivers from the compact actuator a quantity of clathrate equivalent to 42 mcg of beclomethasone dipropionate, USP.
The contents of one 6.7-g canister provide at least 80 metered doses, and the contents of one 16.8-g canister provide at least 200 metered doses.
Beclomethasone 17,21-dipropionate is a diester of beclomethasone, a synthetic halogenated corticosteroid. Animal studies show that beclomethasone dipropionate has potent glucocorticoid and weak mineralocorticoid activity.
The mechanisms responsible 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 with beclomethasone dipropionate by the intranasal route 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 1,000 mcg per day for 1 month as an oral aerosol or for 3 days by intramuscular injection. However, partial suppression of plasma cortisol concentrations was observed when beclomethasone dipropionate was administered in doses of 2,000 mcg per day either by oral aerosol or intramuscular injection. Immediate suppression of plasma cortisol concentrations was observed after single doses of 4,000 mcg of beclomethasone dipropionate. Suppression of HPA function (reduction of early morning plasma cortisol levels) has been reported in adult patients who received 1,600-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%.
BECONASE Inhalation Aerosol is indicated for the relief of the symptoms of seasonal or perennial rhinitis in those cases poorly responsive to conventional treatment.
BECONASE Inhalation Aerosol is also indicated for the prevention of recurrence of nasal polyps following surgical removal.
Clinical studies in patients with seasonal or 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, BECONASE Inhalation Aerosol should not be continued beyond 3 weeks in the absence of significant symptomatic improvement. BECONASE Inhalation Aerosol 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.
Hypersensitivity to any of the ingredients of this preparation contraindicates its use.
The replacement of a systemic corticosteroid with BECONASE Inhalation 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 BECONASE Inhalation 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 increases the likelihood of HPA suppression compared to a therapeutic dose of either one alone. Therefore, BECONASE Inhalation Aerosol 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, cataracts, and cushingoid features. If such changes occur, BECONASE Inhalation Aerosol should be discontinued slowly consistent with accepted procedures for discontinuing oral steroid therapy.
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 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.
General: During withdrawal from oral steroids, some patients may experience symptoms of withdrawal, e.g., joint and/or muscular pain, lassitude, and depression.
Rare instances of nasal septum perforation have been spontaneously reported.
Rare instances of wheezing, cataracts, glaucoma, and increased intraocular pressure have been reported following the intranasal use of beclomethasone dipropionate.
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 discontinuation of treatment with BECONASE Inhalation Aerosol.
Beclomethasone dipropionate is absorbed into the circulation. Use of excessive doses of BECONASE Inhalation Aerosol may suppress HPA function.
BECONASE Inhalation Aerosol should be used with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract; untreated fungal, bacterial, or systemic viral infections; or ocular herpes simplex.
For BECONASE Inhalation 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 BECONASE Inhalation Aerosol should be considered adjunctive therapy to surgical removal and/or the use of other medications that will permit effective penetration of BECONASE Inhalation Aerosol into the nose. Nasal polyps may recur after any form of treatment.
As with any long-term treatment, patients using BECONASE Inhalation Aerosol 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.
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 BECONASE Inhalation 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 BECONASE Inhalation Aerosol are fully manifested. One to 2 weeks may pass before full relief is obtained. The patient should contact the physician 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 carefully the patient' instructions section of the package insert.
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 Teratogenic Effects: 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 10 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 10 times the human dose or orally at 1,000 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 BECONASE Inhalation Aerosol is administered to a nursing woman.
Pediatric Use: Safety and effectiveness in children below 6 years of age have not been established.
In general, side effects in clinical studies have been primarily associated with the nasal mucous membranes.
Adverse reactions reported in controlled clinical trials and long-term open studies in patients treated with BECONASE Inhalation Aerosol are described below.
Sensations of irritation and burning in the nose (11 per 100 patients) following the use of BECONASE Inhalation Aerosol have been reported. Also, occasional sneezing attacks (10 per 100 adult 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 have been reported in 2 per 100 patients.
Rare cases of ulceration of the nasal mucosa and instances of nasal septum perforation have been spontaneously reported (see PRECAUTIONS ).
Reports of headache, light-headedness, 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.
Rare instances of wheezing, cataracts, glaucoma, and increased intraocular pressure have been reported following the use of intranasal beclomethasone dipropionate (see PRECAUTIONS ).
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.
Systemic corticosteroid side effects were not reported during the controlled clinical trials. If recommended doses are exceeded, however, or if individuals are particularly sensitive, symptoms of hypercorticism, i.e., Cushing' syndrome, could occur.
When used at excessive doses, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, BECONASE Inhalation 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 BECONASE Inhalation Aerosol contains 8.4 mg of beclomethasone dipropionate; therefore, acute overdosage is unlikely.
Adults and Children 12 Years of Age and Older: The usual dosage is one inhalation (42 mcg) in each nostril two to four times a day (total dose, 168 to 336 mcg per day). Patients can often be maintained on a maximum dose of one inhalation in each nostril three times a day (252 mcg per day).
Children 6 to 12 Years of Age: The usual dosage is one inhalation in each nostril three times a day (252 mcg per day). BECONASE Inhalation Aerosol is not recommended for children below 6 years of age since safety and efficacy studies have not been conducted in this age-group.
In patients who respond to BECONASE Inhalation Aerosol, an improvement of the symptoms of seasonal or perennial rhinitis usually becomes apparent within a few days after the start of BECONASE Inhalation Aerosol therapy. However, symptomatic relief may not occur in some patients for as long as 2 weeks. BECONASE Inhalation Aerosol should not be continued beyond 3 weeks in the absence of significant symptomatic improvement.
The therapeutic effects of corticosteroids, unlike those of decongestants, 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.
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 BECONASE Inhalation Aerosol therapy.
Directions for Use: Illustrated Patient' Instructions for Use accompany each package of BECONASE 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.
BECONASE Inhalation Aerosol is supplied in a 6.7-g canister containing 80 metered doses (NDC 0173-0468-00) and in a 16.8-g canister containing 200 metered doses (NDC 0173-0336-02), each with beige compact actuator and patient' instructions.
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. Shake well before using.
Glaxo Wellcome Inc., Research Triangle Park, NC 27709
May 1997/RL-424
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