BECONASE AQ

BECONASE AQ- beclomethasone dipropionate monohydrate spray, suspension
GlaxoSmithKline LLC

DESCRIPTION

Beclomethasone dipropionate, monohydrate, the active component of BECONASE AQ Nasal Spray, is an anti-inflammatory steroid having the chemical name 9-chloro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 17,21-dipropionate, monohydrate and the following chemical structure:

Beclomethasone dipropionate, monohydrate chemical structure

Beclomethasone 17,21-dipropionate is a diester of beclomethasone, a synthetic halogenated corticosteroid. Beclomethasone dipropionate, monohydrate is a white to creamy-white, odorless powder with a molecular weight of 539.06. It is very slightly soluble in water, very soluble in chloroform, and freely soluble in acetone and in ethanol.

BECONASE AQ Nasal Spray is a metered-dose, manual pump spray unit containing a microcrystalline suspension of beclomethasone dipropionate, monohydrate equivalent to 42 mcg of beclomethasone dipropionate, calculated on the dried basis, in an aqueous medium containing microcrystalline cellulose, carboxymethylcellulose sodium, dextrose, benzalkonium chloride, polysorbate 80, and 0.25% v/w phenylethyl alcohol. The pH through expiry is 5.0 to 6.8.

After initial priming (6 actuations), each actuation of the pump delivers from the nasal adapter 100 mg of suspension containing beclomethasone dipropionate, monohydrate equivalent to 42 mcg of beclomethasone dipropionate. If the pump is not used for 7 days, it should be primed until a fine spray appears. Each 25-g bottle of BECONASE AQ Nasal Spray provides 180 metered sprays.

CLINICAL PHARMACOLOGY

Mechanism of Action:

Following topical administration, beclomethasone dipropionate produces anti-inflammatory and vasoconstrictor effects. The mechanisms responsible for the anti-inflammatory action of beclomethasone dipropionate are unknown. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation. The direct relationship of these findings to the effects of beclomethasone dipropionate on allergic rhinitis symptoms is not known.

Biopsies of nasal mucosa obtained during clinical studies showed no histopathologic changes when beclomethasone dipropionate was administered intranasally.

Beclomethasone dipropionate is a pro-drug with weak glucocorticoid receptor binding affinity. It is hydrolyzed via esterase enzymes to its active metabolite beclomethasone-17-monopropionate (B-17-MP), which has high topical anti-inflammatory activity.

Pharmacokinetics:

Absorption: Beclomethasone dipropionate is sparingly soluble in water. When given by nasal inhalation in the form of an aqueous or aerosolized suspension, the drug is deposited primarily in the nasal passages. The majority of the drug is eventually swallowed. Following intranasal administration of aqueous beclomethasone dipropionate, the systemic absorption was assessed by measuring the plasma concentrations of its active metabolite B-17-MP, for which the absolute bioavailability following intranasal administration is 44% (43% of the administered dose came from the swallowed portion and only 1% of the total dose was bioavailable from the nose). The absorption of unchanged beclomethasone dipropionate following oral and intranasal dosing was undetectable (plasma concentrations <50 pg/mL).

Distribution: The tissue distribution at steady state for beclomethasone dipropionate is moderate (20 L) but more extensive for B-17-MP (424 L). There is no evidence of tissue storage of beclomethasone dipropionate or its metabolites. Plasma protein binding is moderately high (87%).

Metabolism: Beclomethasone dipropionate is cleared very rapidly from the systemic circulation by metabolism mediated via esterase enzymes that are found in most tissues. The main product of metabolism is the active metabolite (B-17-MP). Minor inactive metabolites, beclomethasone-21-monopropionate (B-21-MP) and beclomethasone (BOH), are also formed, but these contribute little to systemic exposure.

Elimination: The elimination of beclomethasone dipropionate and B-17-MP after intravenous administration are characterized by high plasma clearance (150 and 120 L/hour) with corresponding terminal elimination half-lives of 0.5 and 2.7 hours. Following oral administration of tritiated beclomethasone dipropionate, approximately 60% of the dose was excreted in the feces within 96 hours, mainly as free and conjugated polar metabolites. Approximately 12% of the dose was excreted as free and conjugated polar metabolites in the urine. The renal clearance of beclomethasone dipropionate and its metabolites is negligible.

Pharmacodynamics:

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/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/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 aerosol intranasally, there was no evidence of adrenal insufficiency. The effect of BECONASE AQ Nasal Spray on HPA function was not evaluated but would not be expected to differ from intranasal beclomethasone dipropionate aerosol.

In 1 study in children with asthma, the administration of inhaled beclomethasone at recommended daily doses for at least 1 year was associated with a reduction in nocturnal cortisol secretion. The clinical significance of this finding is not clear. It reinforces other evidence, however, that topical beclomethasone may be absorbed in amounts that can have systemic effects and that physicians should be alert for evidence of systemic effects, especially in chronically treated patients (see PRECAUTIONS).

INDICATIONS AND USAGE

BECONASE AQ Nasal Spray is indicated for the relief of the symptoms of seasonal or perennial allergic and nonallergic (vasomotor) rhinitis.

Results from 2 clinical trials have shown that significant symptomatic relief was obtained within 3 days. However, symptomatic relief may not occur in some patients for as long as 2 weeks. BECONASE AQ Nasal Spray should not be continued beyond 3 weeks in the absence of significant symptomatic improvement. BECONASE AQ Nasal Spray should not be used in the presence of untreated localized infection involving the nasal mucosa.

BECONASE AQ Nasal Spray is also indicated for the prevention of recurrence of nasal polyps following surgical removal.

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.

WARNINGS

The replacement of a systemic corticosteroid with BECONASE AQ Nasal Spray 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 AQ Nasal Spray. 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.

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 AQ Nasal Spray should be discontinued slowly consistent with accepted procedures for discontinuing oral steroid therapy.

Persons who are using 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 susceptible children or adults using corticosteroids. In children or adults who have not had these diseases or been properly immunized, 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.

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