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Beclomethasone dipropionate, monohydrate, the active component of VANCENASE AQ 84 mcg Nasal Spray, 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, monohydrate and the following chemical structure:
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Beclomethasone dipropionate, monohydrate, is a white to creamy-white, odorless powder with a molecular formula of C 28 H 37 ClO 7 ·H 2 O and 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.
After initial priming (at least 6 actuations) of VANCENASE AQ 84 mcg Nasal Spray, each actuation of the pump delivers 100 mg of suspension containing beclomethasone dipropionate, monohydrate equivalent to 84 mcg beclomethasone dipropionate. Each bottle of VANCENASE AQ 84 mcg Nasal Spray will provide at least 120 actuations.
VANCENASE AQ 84 mcg Nasal Spray is a metered-dose, manual pump spray unit containing a suspension of beclomethasone dipropionate, monohydrate equivalent to 0.084% w/w beclomethasone dipropionate in an aqueous medium containing microcrystalline cellulose, carboxymethylcellulose sodium, dextrose, benzalkonium chloride, polysorbate 80, and phenylethyl alcohol. The suspension is formulated at a target pH of 6.4, with a range of 5.5 to 6.8 over its shelf life.
Beclomethasone 17,21-dipropionate is a diester of beclomethasone, a synthetic halogenated corticosteroid. Animal studies show that beclomethasone dipropionate has potent glucocorticosteroid and weak mineralcorticosteroid 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 (duration of treatment from 1 to 6 years at doses up to 336 mcg/day) showed no histopathologic changes when beclomethasone dipropionate was administered intranasally.
In a study evaluating the hypothalamic-pituitary-adrenal (HPA) effects of 336 mcg/day beclomethasone dipropionate administered intranasally for 36 consecutive days via aqueous suspension, there was no statistically significant difference in cortisol suppression between beclomethasone dipropionate 336 mcg once daily, beclomethasone dipropionate 168 mcg twice daily, and placebo. Plasma cortisol response to 6-hour cosyntropin stimulation was attenuated in control patients who received oral prednisone 10 mg daily.
The effects of beclomethasone dipropionate on HPA function have also been evaluated in adult volunteers by other routes 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 intramuscular injection. 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 one study of pediatric patients with asthma, the administration of inhaled beclomethasone dipropionate 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 dipropionate 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 beclomethasone (which has very weak anti-inflammatory activity). However, irrespective of the route of entry, the principal route of excretion is the feces. In humans, 12% to 15% of an orally administered dose of beclomethasone dipropionate is excreted in the urine. The drug is excreted in both urine and feces as free and conjugated polar metabolites.
Studies have shown that the degree of binding to plasma proteins is 87%.
In clinical trials with VANCENASE AQ 84 mcg Nasal Spray in patients with seasonal allergic rhinitis, 336 mcg of beclomethasone dipropionate once daily was superior to placebo with respect to effects on nasal symptoms. In a study comparing VANCENASE AQ 84 mcg Nasal Spray once daily with beclomethasone dipropionate 42 mcg nasal spray twice daily, each delivering a total daily dose of 336 mcg beclomethasone dipropionate, both regimens were comparable with respect to effects on physician-rated nasal symptoms. In this study, a significant advantage over placebo was observed for both regimens within 3 days of the start of treatment.
VANCENASE AQ 84 mcg Nasal Spray is indicated for the relief of symptoms of allergic and nonallergic (vasomotor) rhinitis. Results from clinical trials of intranasal beclomethasone dipropionate in patients with seasonal allergic rhinitis have shown that significant symptom relief was obtained in most patients within 3 days. However, symptom relief may not occur in some patients for as long as 2 weeks. VANCENASE AQ 84 mcg Nasal Spray should not be continued beyond 3 weeks in the absence of significant symptom improvement. VANCENASE AQ 84 mcg Nasal Spray should not be used in the presence of untreated localized infection involving the nasal mucosa.
VANCENASE AQ 84 mcg Nasal Spray is also indicated for the prevention of recurrence of nasal polyps following surgical removal.
Clinical studies with beclomethasone dipropionate 42 mcg nasal spray 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 VANCENASE AQ 84 mcg Nasal Spray can be accompanied by signs of adrenal insufficiency.
When transferred to VANCENASE AQ 84 mcg Nasal Spray, careful attention must be given to patients previously treated for prolonged periods with systemic corticosteroids. 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 dipropionate 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 AQ 84 mcg Nasal Spray should be discontinued slowly, consistent with accepted procedures for discontinuing 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 or adult patients on corticosteroids. In such pediatric or adult patients 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, eg, joint and/or muscular pain, lassitude, and depression.
Rarely, immediate hypersensitivity reactions may occur after the intranasal administration of beclomethasone. Rare instances of nasal septum perforation have been reported.
Rare instances of wheezing and increased intraocular pressure have been reported following the intranasal application of aerosolized corticosteroids. Although these have not been observed in clinical trials with VANCENASE AQ 84 mcg Nasal Spray, vigilance should be maintained.
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, use of VANCENASE AQ 84 mcg Nasal Spray should be discontinued and appropriate local or systemic therapy instituted, if needed.
If persistent nasopharyngeal irritation occurs, VANCENASE AQ 84 mcg Nasal Spray should be discontinued.
Beclomethasone dipropionate is absorbed into the circulation. Use of excessive doses of VANCENASE AQ 84 mcg Nasal Spray may suppress HPA function.
VANCENASE AQ 84 mcg Nasal Spray 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 AQ 84 mcg Nasal Spray to be effective in the treatment of nasal polyps, the spray must be able to enter the nose. Therefore, treatment of nasal polyps with VANCENASE AQ 84 mcg Nasal Spray should be considered adjunctive therapy to surgical removal and/or the use of other medications which will permit effective penetration of VANCENASE AQ 84 mcg Nasal Spray into the nose. Nasal polyps may recur after any form of treatment.
As with any long-term treatment, patients using VANCENASE AQ 84 mcg Nasal Spray 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 corticosteroid intranasally 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 being treated with VANCENASE AQ 84 mcg Nasal Spray should receive the following information and instructions. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. Patients should use VANCENASE AQ 84 mcg Nasal Spray ONLY once daily at a regular interval. Improvement usually becomes apparent within 3 days after the start of therapy. However, 1 to 2 weeks may pass before full relief is obtained. Since VANCENASE AQ 84 mcg Nasal Spray is not immediately effective, the prescribed dosage of VANCENASE AQ 84 mcg Nasal Spray should not be increased by using it more often than once a day in an attempt to increase its efficacy. Instead, nasal vasoconstrictors or oral antihistamines may be needed until the effects of VANCENASE AQ 84 mcg Nasal Spray are fully manifested. The patient should contact the physician if symptoms do not improve, or if the condition worsens, or if sneezing or nasal irritation occurs. For the proper use of this unit and to attain maximum benefit, the patient should read and follow the accompanying Patient' Instructions carefully.
Patients should be warned not to spray VANCENASE AQ 84 mcg Nasal Spray into the eyes.
Persons who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles, and patients should also be advised that if they are exposed, medical advice should be sought without delay.
Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenicity of beclomethasone dipropionate was evaluated in rats which were treated for a total of 95 weeks, 13 weeks at inhalation doses up to 0.4 mg/kg/day and the remaining 82 weeks at combined oral and inhalation doses up to 2.4 mg/kg/day (approximately 40 times the maximum recommended human daily intranasal dose on a mg/m 2 basis). There was no evidence of carcinogenicity in this study. Studies to assess the mutagenic potential of beclomethasone dipropionate have not been conducted. Impairment of fertility, as evidenced by inhibition of the estrous cycle in dogs, was observed following treatment by the oral route at a dose of 0.5 mg/kg/day (approximately 40 times the maximum recommended human daily intranasal dose on a mg/m 2 basis). No inhibition of the estrous cycle in dogs was seen following 12 months of exposure to beclomethasone dipropionate by the inhalation route at an estimated weekly dose of 2.3 mg/kg (approximately 26 times the maximum recommended human weekly intranasal dose on a mg/m 2 basis
Pregnancy Category C: Like other corticosteroids, parenteral (subcutaneous) beclomethasone dipropionate has been shown to be teratogenic and embryocidal in the mouse and rabbit when given at a dose of 0.1 mg/kg/day in mice and at a dose of 0.025 mg/kg/day in rabbits (approximately 1.2 times the maximum recommended human daily intranasal dose on a mg/m 2 basis). No teratogenic or embryocidal effects have been seen in rats treated with beclomethasone by combined inhalation and oral administration at doses of 0.1 mg/kg/day and 10 mg/kg/day, respectively (approximately 250 times the maximum recommended human daily intranasal dose on a mg/m 2 basis). 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 AQ 84 mcg Nasal Spray is administered to nursing women.
Pediatric Use: Safety and effectiveness of VANCENASE AQ 84 mcg Nasal Spray in pediatric patients below the age of 6 years have not been established.
In clinical studies with intranasally administered beclomethasone dipropionate, adverse effects have primarily been related to irritation of the nasal mucous membranes. Rarely, immediate hypersensitivity reactions may occur after intranasal administration of beclomethasone dipropionate.
Clinical trials of VANCENASE AQ 84 mcg Nasal Spray included 187 patients who received VANCENASE AQ 84 mcg Nasal Spray, 127 patients who received beclomethasone dipropionate 42 mcg nasal spray, and 192 patients who received vehicle placebo. The incidence and nature of adverse events with VANCENASE AQ 84 mcg Nasal Spray (336 mcg beclomethasone dipropionate once daily) was comparable to that seen with beclomethasone dipropionate 42 mcg nasal spray (168 mcg beclomethasone dipropionate twice daily) and with vehicle placebo. Adverse events reported by 2% or more of patients (regardless of relationship to treatment) who received VANCENASE AQ 84 mcg Nasal Spray in clinical trials and that were more common with VANCENASE AQ 84 mcg Nasal Spray than with placebo are displayed in the table below.
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Rare cases of ulceration of the nasal mucosa and instances of nasal septum perforation have been reported following the intranasal administration of beclomethasone dipropionate (see PRECAUTIONS ).
Rare instances of wheezing and increased intraocular pressure have been reported following the intranasal administration of aerosolized corticosteroids (see PRECAUTIONS ).
Single cases each of aseptic necrosis of the femoral head and of nasal fungal infection with erosion through the cribriform plate have been reported after long-term administration of beclomethasone dipropionate nasal spray.
When used at excessive doses, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, VANCENASE AQ 84 mcg Nasal Spray should be discontinued slowly consistent with accepted procedures for discontinuing oral steroid therapy. The oral median lethal dose of beclomethasone dipropionate is greater than 1 g/kg in mice and rats (approximately 7000 times and 14,000 times, respectively, the maximum recommended human daily intranasal dose on a mg/m 2 basis). One bottle of VANCENASE AQ 84 mcg Nasal Spray contains beclomethasone dipropionate, monohydrate equivalent to 16.0 mg of beclomethasone dipropionate; therefore, acute overdosage is unlikely.
Adults and Pediatric Patients 6 Years of Age and Over: The usual dosage of VANCENASE AQ 84 mcg Nasal Spray is 1 or 2 inhalations in each nostril once daily (total dose 168-336 mcg/day).
In patients who respond to VANCENASE AQ 84 mcg Nasal Spray, an improvement of the symptoms of allergic rhinitis usually becomes apparent within a few days after the start of therapy. Patients should use VANCENASE AQ 84 mcg Nasal Spray ONLY once daily at a regular interval. VANCENASE AQ 84 mcg Nasal Spray is not acutely effective, therefore, the prescribed dosage of VANCENASE AQ 84 mcg Nasal Spray should not be increased by using it more often than once daily. Symptom relief may not occur in some patients for as long as 2 weeks. VANCENASE AQ 84 mcg Nasal Spray should not be continued beyond 3 weeks in the absence of significant symptom improvement.
Since the therapeutic effects of corticosteroids, unlike those of a decongestant on allergic 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 AQ 84 mcg Nasal Spray 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 sites of intended action. In such cases it is advisable to use a topical or oral nasal vasoconstrictor/decongestant during the first 2 to 3 days of VANCENASE AQ 84 mcg Nasal Spray therapy.
Prior to initial use of VANCENASE AQ 84 mcg Nasal Spray, the pump must be primed by actuating six times or until a fine spray appears. If the pump is unused for more than 4 days, repriming may be necessary. To reprime the unit, spray once or until a fine spray appears.
Directions for Use: Illustrated Patient' Instructions for proper use accompany each package of VANCENASE AQ 84 mcg Nasal Spray.
VANCENASE AQ 84 mcg (beclomethasone dipropionate, monohydrate) Nasal Spray, 19 g net weight, 120 actuations, white high-density polyethylene bottle fitted with a white metered-dose nasal spray pump, maroon safety clip, and white dust cap; box of one. Supplied with Patient' Instructions for Use (NDC 0085-1049-01).
Store between 2° and 25°C (36° and 77°F).
SHAKE WELL BEFORE EACH USE.
Schering Corporation
Kenilworth, NJ 07033 USA
Copyright © 1996, 1997, Schering Corporation. All rights
reserved. Rev. 4/97
18802333
18780941T
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