BECONASE

DESCRIPTION

Beclomethasone dipropionate is an anti-inflammatory corticosteroid having the chemical name 9-chloro-11b,17,21-trihydroxy-16b-methylpregna-1,4-diene-3,20-doine17,21-dipropionate.

Nasal Inhalation

Beclomethasone dipropionate is a white to creamy white, odorless powder a molecular weight of 521.25 (double strength 521.05). It is very slightly soluble in water, very soluble in chloroform, and freely soluble in acetone and in alcohol.

Beclomethasone dipropionate nasal inhalers are pressurized metered-dose aerosol units 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.

Beconase (beclomethasone nasal) Nasal Inhaler: Each actuation delivers from the compact actuator a quantity of clathrate equivalent to 42 mcg of beclomethasone dipropionate. The contents of one 6.7 g-nasal inhaler canister provide at least 80 metered doses and the contents of one 16.8 g-nasal inhaler canister provide at least 200 metered doses.

Nasal Spray

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 alcohol.

This form is a metered-dose, manual pump spray unit containing a microcrystalline suspension of beclomethasone dipropionate, monohydrate equivalent to 0.042% w/w 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; hydrochloric acid may be added to adjust pH. The pH is between 4.5 and 7.0.

After initial priming (3 to 4 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. Each bottle of Beconase (beclomethasone nasal) AQ nasal spray delivers at least 200 metered doses.

INDICATIONS

Beclomethasone dipropionate nasal inhaler and nasal spray is indicated in the relief of the symptoms of seasonal or perennial allergic and nonallergic (vasomotor) rhinitis in those cases poorly responsive to conventional treatment.

Results from two 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. Beclomethasone dipropionate nasal spray should not be continued beyond 3 weeks in the absence of significant symptomatic improvement. Beclomethasone dipropionate nasal spray should not be used in the presence of untreated localized infection involving the nasal mucosa.

Beclomethasone dipropionate nasal inhaler and spray is also indicated for the prevention of recurrence of nasal polyps following surgical removal.

Clinical studies using the nasal inhalation aerosol 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, beclomethasone dipropionate nasal inhaler and nasal spray should not be continued beyond 3 weeks in the absence of significant systematic improvement. Beclomethasone dipropionate nasal inhaler and nasal spray 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 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.

DOSAGE AND ADMINISTRATION

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

The therapeutic effect 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 mucous 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 beclomethasone dipropionate therapy.

Nasal Inhaler

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). This product is not recommended for children under 6 years of age since safety and efficacy studies have not been conducted in this age-group.

Nasal Spray

Adults and Children 12 Years of Age and Older: The usual dosage is one or two inhalations (42 to 84 mcg) in each nostril twice a day (total dose, 168 to 336 mcg per day).

Children 6 to 12 Years of Age: Patients should be started with one inhalation in each nostril twice a day; patients not adequately responding to 168 mcg or those with more severe symptoms may use 336 mcg (two inhalations in each nostril). Beclomethasone dipropionate nasal spray is not recommended for children below 6 years of age.

HOW SUPPLIED

Nasal Inhalers: 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 in fire or incinerator. Keep out of reach of children.

Store between 2–30°C (36–86°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.

Nasal Spray: Store between 15–30°C (59–86°F). Shake well before each use.

SIDE EFFECTS

Nasal Inhaler

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 beclomethasone dipropionate nasal inhaler are described below.

Sensations of irritation and burning in the nose (11 per 100 patients) following the use of beclomethasone dipropionate nasal inhaler 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 intranasal application of aerosolized corticosteroids (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’s syndrome, could occur).

Nasal Spray

In general, side effects in clinical studies have been primarily associated with irritation of the nasal mucous membranes. 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 dipropionate.

Adverse reactions reported in controlled clinical trials and open studies in patients treated with beclomethasone dipropionate nasal spray are described below.

Mild nasopharyngeal irritation following the use of beclomethasone aqueous nasal spray has been reported in up to 24% of patients treated, including occasional sneezing attacks (about 4%) occurring immediately following use of the spray. In patients experiencing these symptoms, none had to discontinue treatment. The incidence of transient irritation and sneezing was approximately the same in the group of patients who received placebo in these studies, implying that these complaints may be related to vehicle components of the formulation.

Fewer than 5 per 100 patients reported headache, nausea, or lightheadedness following the use of beclomethasone dipropionate nasal spray. Fewer than 3 per 100 patients reported nasal stuffiness, nosebleeds, rhinorrhea, or tearing eyes.

Rare cases of ulceration of the nasal mucosa and instances of nasal septum perforation have been spontaneously reported (see PRECAUTIONS).

Reports of 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 (see PRECAUTIONS).

DRUG INTERACTIONS

No information provided.

WARNINGS

The replacement of a systemic corticosteroid with beclomethasone dipropionate nasal inhaler or 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 beclomethasone dipropionate nasal inhaler or 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.

Studies have shown that combined administration of alternate-day prednisone systemic treatment and orally inhaled beclomethasone dipropionate increases the likelihood of HPA suppression compared to a therapeutic dose of either one alone. Therefore, nasal forms of beclomethasone dipropionate 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, acneform lesions, cataracts, and cushingoid features. If such changes occur, this drug 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 of these infectious agents. 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 of developing a more severe infection 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 intramuscualr immunoglobulin (IG), may be indicated. (See the respective product information 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 (e.g., joint and/or muscular pain, lassitude, and depression).

Rarely, immediate hypersensitivity reactions may occur after the intranasal administration of beclomethasone (see ADVERSE REACTIONS).

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 application of beclamthasone.

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 discontinued use of treatment.

If persistent nasopharyngeal irritation occurs, it may be an indication for stopping beclomethasone dipropionate administered intranasally.

Beclomethasone dipropionate is absorbed into the circulation. Use of excessive doses may suppress HPA function.

This drug 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 intranasal forms of beclomethasone dipropionate to be effective in the treatment of nasal polyps, the aerosol or spray must be able to enter the nose. Therefore, treatment of nasal polyps with beclomethasone dipropionate should be considered adjunctive therapy to surgical removal and/or the use of other medications which will permit effective penetration of this drug into the nose. Nasal polyps may recur after any form of treatment.

As with any long-term treatment, patients using intranasal beclomethasone dipropionate 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 septal 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 the Patient

See PATIENT INFORMATION section.

Carcinogenesis, Mutagenesis, and 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 by the inhalation route.

Pregnancy Category C

Teratogenic Effects: Like other corticoids, parenteral (subcutaneous) beclomethasone dipropionate has 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 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 beclomethasone dipropionate nasal spray is administered to a nursing woman.

Pediatric Use

Nasal Spray: The safety and effectiveness of beclomethasone dipropionate nasal spray have been established in children aged 6 years and above through evidence from extensive clinical use in adult and pediatric patients. The safety and effectiveness of beclomethasone dipropionate nasal spray in children below 6 years of age have not been established.

Glucocorticoids have been shown to cause a reduction in growth velocity in children and teenagers with extended use. If a child or teenager on any glucocorticoid appears to have growth suppression, the possibility that they are particularly sensitive to this effect of glucocorticoids should be considered.

Nasal Inhalation: Safety and effectiveness in children below 6 years of age have not been established.

OVERDOSE

When used at excessive doses, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, beclomethasone dipropionate intranasal should be discontinued slowly consistent with accepted procedures for discontinuing oral steroid therapy. The oral LD₅₀ of beclomethasone dipropionate is greater that 1 g/kg in rodents. One canister of beclomethasone dipropionate nasal inhaler contains 8.4 mg of beclomethasone dipropionate, and one bottle of beclomethasone dipropionate nasal spray contains beclomethasone dipropionate, monohydrate equivalent to 10.5 mg of beclomethasone dipropionate; therefore, acute overdosage is unlikely.

CONTRAINDICATIONS

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

CLINICAL PHARMACOLOGY

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’s 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 effect 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 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 per day for 1 month as an oral aerosol or for 3 days by IM injection. However, partial suppression of plasma cortisol concentration was observed when beclomethasone dipropionate was administered in doses of 2000 mcg per day either by oral aerosol or intramuscular injection form. Immediate suppression of plasma cortisol concentrations was observed after single doses of 4000 mcg of beclomethasone dipropionate. Suppression of HPA function (reduced 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.

The effect of beclomethasone dipropionate nasal spray on HPA function was not evaluated but would not be expected to differ from intranasal beclomethasone dipropionate aerosol.

In one study in asthmatic children, 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).

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 becloethasone (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%.