Beconase Aqueous

Beconase Aqueous uses

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Beconase Aqueous reviews

1 INDICATIONS AND USAGE

Beconase Aqueous Nasal Aerosol is a corticosteroid indicated for the treatment of nasal symptoms associated with seasonal and perennial allergic rhinitis in patients 4 years of age and older.

1.1 Treatment of Nasal Symptoms of Allergic Rhinitis

Beconase Aqueous^® Nasal Aerosol is indicated for the treatment of the nasal symptoms associated with seasonal and perennial allergic rhinitis in patients 4 years of age and older.

2 DOSAGE AND ADMINISTRATION

Administer Beconase Aqueous Nasal Aerosol by the intranasal route only. Beconase Aqueous Nasal Aerosol must be primed prior to initial use by actuating four times. To do this, remove the protective dust cap from the device, hold the device upright between your thumb and forefinger (the canister should be on top, pointing down), and spray 4 times into the air, away from your eyes and face. After the initial priming, the dose counter should read 120 for Beconase Aqueous 40 mcg Nasal Aerosol and Beconase Aqueous 80 mcg Nasal Aerosol 120-actuation products and 60 for Beconase Aqueous 40 mcg Nasal Aerosol 60-actuation product. If Beconase Aqueous Nasal Aerosol is not used for 7 consecutive days it should be primed by spraying 2 times. See accompanying illustrated Patient Information and Instructions for Use leaflet for proper use of Beconase Aqueous Nasal Aerosol.

Beconase Aqueous Nasal Aerosol is for intranasal use only.

• The recommended dose of Beconase Aqueous 80 mcg Nasal Aerosol in patients 12 years and older is 320 mcg per day administered as 2 actuations in each nostril once daily (maximum total daily dose of 4 actuations per day). ( 2.1 )
• The recommended dose of Beconase Aqueous 40 mcg Nasal Aerosol in children aged 4 to 11 years of age is 80 mcg per day administered as 1 actuation in each nostril once daily (maximum total daily dose of 2 actuations per day). ( 2.1 )

2.1 Allergic Rhinitis

Adults and Adolescents (12 Years of Age and Older): The recommended dose of Beconase Aqueous Nasal Aerosol is 320 mcg per day administered as 2 actuations in each nostril (QNASL 80 mcg Nasal Aerosol) once daily (maximum total daily dose of 4 actuations per day).

Children (4 to 11 Years of Age): The recommended dose of Beconase Aqueous Nasal Aerosol is 80 mcg per day administered as 1 actuation in each nostril (QNASL 40 mcg Nasal Aerosol) once daily (maximum total daily dose of 2 actuations per day).

3 DOSAGE FORMS AND STRENGTHS

Beconase Aqueous Nasal Aerosol is a nonaqueous nasal spray solution.

Each actuation of Beconase Aqueous 40 mcg Nasal Aerosol delivers 40 mcg of Beconase Aqueous and each actuation of Beconase Aqueous 80 mcg Nasal Aerosol delivers 80 mcg of Beconase Aqueous. Each strength is supplied in an 8.7 g canister containing 120 actuations; Beconase Aqueous 40 mcg Nasal Aerosol is also supplied in a 4.9 g canister containing 60 actuations.

Beconase Aqueous Nasal Aerosol is available in two strengths:

• Each actuation of Beconase Aqueous 40 mcg Nasal Aerosol delivers 40 mcg of Beconase Aqueous. ( 3 )
• Each actuation of Beconase Aqueous 80 mcg Nasal Aerosol delivers 80 mcg of Beconase Aqueous. ( 3 )
• Each strength is supplied in an 8.7 g canister containing 120 actuations; Beconase Aqueous 40 mcg Nasal Aerosol is also supplied in a 4.9 g canister containing 60 actuations. ( 3 )

4 CONTRAINDICATIONS

Beconase Aqueous Nasal Aerosol is contraindicated in patients with a history of hypersensitivity to Beconase Aqueous and/or any other Beconase Aqueous Nasal Aerosol ingredients .

Patients with a history of hypersensitivity to Beconase Aqueous and/or any other Beconase Aqueous Nasal Aerosol ingredients. ( 4 )

5 WARNINGS AND PRECAUTIONS

• Nasal discomfort, epistaxis, nasal ulceration, Candida albicans infection, nasal septal perforation, impaired wound healing. Monitor patients periodically for signs of adverse effects on the nasal mucosa. Avoid use in patients with recent nasal ulcers, nasal surgery, or nasal trauma.
• Eye Disorders. Monitor patients closely with a change in vision or with a history of increased intraocular pressure, blurred vision, glaucoma, and/or cataracts. ( 5.2 )
• Hypersensitivity, rash, and urticaria may occur after administration of Beconase Aqueous Nasal Aerosol. ( 5.3 )
• Potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. More serious or even fatal course of chickenpox or measles in susceptible patients. Use caution in patients with the above because of the potential for worsening of these infections. ( 5.4 )
• Hypercorticism and adrenal suppression with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue Beconase Aqueous Nasal Aerosol slowly. ( 5.5 )
• Potential reduction in growth velocity in pediatric patients. Monitor growth routinely in pediatric patients receiving Beconase Aqueous Nasal Aerosol. ( 5.6, 8.4 )

5.1 Local Nasal Effects

Nasal Discomfort, Epistaxis, and Nasal Ulceration: In clinical trials of 2 to 52 weeks duration, epistaxis and nasal ulcerations were observed more frequently and some epistaxis events were more severe in patients treated with Beconase Aqueous Nasal Aerosol than those who received placebo. In the 52-week safety trial in patients with perennial allergic rhinitis, nasal erosions were identified in 4 of 415 patients and a nasal ulceration was identified in 1 of 415 patients treated with Beconase Aqueous Nasal Aerosol. No nasal erosions or ulcerations were reported for patients who received placebo. In clinical trials conducted in pediatric patients ages 4 to 11 years, the local nasal effect was similar to those reported in patients 12 years of age and older. Patients using Beconase Aqueous Nasal Aerosol over several months or longer should be examined periodically for possible changes in the nasal mucosa. If an adverse reaction (e.g., erosion, ulceration) is noted, discontinue Beconase Aqueous Nasal Aerosol .

Candida Infection: In previous clinical trials with an aqueous formulation of Beconase Aqueous administered intranasally, localized infections of the nose and pharynx with Candida albicans had been reported. There were no instances of similar infections observed in clinical trials with Beconase Aqueous Nasal Aerosol. If such an infection develops, it may require treatment with appropriate local therapy and discontinuation of Beconase Aqueous Nasal Aerosol treatment. Thus, patients using Beconase Aqueous Nasal Aerosol over several months or longer should be examined periodically for evidence of Candida infection.

Nasal Septal Perforation: Instances of nasal septal perforation have been reported in patients following the intranasal application of Beconase Aqueous. There were no nasal septal perforations reported during clinical trials in the indicated dose of Beconase Aqueous 80 mcg Nasal Aerosol administered as 320 mcg once daily in adults and adolescents. There was one report of nasal septal perforation observed in the dose-ranging pediatric clinical trial.

Impaired Wound Healing: Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal septal ulcers, nasal surgery, or nasal trauma should not use Beconase Aqueous Nasal Aerosol until healing has occurred.

5.2 Eye Disorders

Use of intranasal and inhaled corticosteroids may result in the development of increased intraocular pressure, blurred vision, glaucoma and/or cataracts. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, blurred vision, glaucoma, and/or cataracts.

Glaucoma and cataract formation was evaluated with ocular assessments that included intraocular pressure measurements and slit lamp examinations in 245 adolescent and adult patients with perennial allergic rhinitis who were treated with Beconase Aqueous Nasal Aerosol 320 mcg daily (N=197) or placebo (N=48) for up to 52 weeks. In 94% of patients, intraocular pressure (IOP) remained within the normal range (<21 mmHg) during the treatment portion of the trial. There were 10 patients (5%) treated with Beconase Aqueous Nasal Aerosol and 1 patient (2%) treated with placebo that had intraocular pressure that increased above normal levels (≥21 mmHg) and greater than baseline during the treatment portion of the trial. Two of these occurrences in patients treated with Beconase Aqueous Nasal Aerosol were reported as adverse reactions, one serious. No instances of cataract formation or other clinically significant ocular incidents were reported in this 52-week safety trial .

5.3 Hypersensitivity Reactions Including Anaphylaxis

Hypersensitivity reactions including anaphylaxis, angioedema, urticaria, and rash have been reported following administration of Beconase Aqueous nasally administered and inhalationally administered products. Angioedema, urticaria, and rash have been reported following administration of Beconase Aqueous Nasal Aerosol. Discontinue Beconase Aqueous Nasal Aerosol if any such reactions occur .

5.4 Immunosuppression

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 a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. If chickenpox or measles develops, treatment with antiviral agents may be considered.

Corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract, untreated local or systemic fungal or bacterial infections, systemic viral or parasitic infections, or ocular herpes simplex because of the potential for worsening of these infections.

5.5 Hypothalamic-Pituitary-Adrenal Axis Effect

When intranasal steroids are used at higher-than-recommended dosages or in susceptible individuals at recommended dosages, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of Beconase Aqueous Nasal Aerosol should be discontinued slowly, consistent with accepted procedures for discontinuing oral corticosteroid therapy.

The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency. In addition, some patients may experience symptoms of corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, and depression). Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress. In patients who have asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, rapid decreases in systemic corticosteroid dosages may cause a severe exacerbation of their symptoms.

5.6 Effect on Growth

Corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Routinely monitor the growth of pediatric patients receiving Beconase Aqueous Nasal Aerosol .

6 ADVERSE REACTIONS

Systemic and local corticosteroid use may result in the following:

• Epistaxis, nasal discomfort, nasal ulcerations, Candida albicans infection, and impaired wound healing
• Eye Disorders
• Hypercorticism, adrenal suppression, and growth reduction [see Warnings and Precautions (5.5) (5.6) , Use in Specific Populations (8.4)]
• Immunosuppression

The most common adverse reactions (≥ 1% and greater than placebo) in patients 12 years of age and older include nasal discomfort, epistaxis, and headache. ( 6.1 )

The most common adverse reactions (≥ 2% and greater than placebo) in children 4 to 11 years of age include headache, pyrexia, upper respiratory tract infection, and nasopharyngitis. ( 6.1 )

To report SUSPECTED ADVERSE REACTIONS, contact Teva Respiratory, LLC at 1-888-482-9522 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adults and Adolescents 12 Years of Age and Older:

The safety data described below for adults and adolescents 12 years of age and older with seasonal or perennial allergic rhinitis are based on 4 placebo-controlled clinical trials of 2 to 6 weeks duration evaluating doses of beclomethasone nasal aerosol from 80 to 320 mcg once daily. These short-term trials included a total of 1394 patients with either seasonal or perennial allergic rhinitis. Of these, 575 (378 female and 197 male) received at least one dose of Beconase Aqueous Nasal Aerosol, 320 mcg once daily and 578 (360 female and 218 male) received placebo. Patient ages ranged from 12 to 82 years and the racial distribution of patients was 81% white, 16% black, and 4% other.

Short-Term (2–6 Weeks) Trials: Less than 2% of patients in the clinical trials discontinued treatment because of adverse reactions with the rate of withdrawal among patients who received Beconase Aqueous Nasal Aerosol similar to or lower than the rate among patients who received placebo. Table 1 displays the common adverse reactions (≥ 1% and greater than placebo-treated patients).

Nasal ulcerations occurred in 2 patients treated with placebo and in 1 patient treated with Beconase Aqueous Nasal Aerosol. There were no differences in the incidence of adverse reactions based on gender or race. Clinical trials did not have sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients.

Long-Term 52-Week Safety Trial: In a 52-week placebo-controlled long-term safety trial in patients with PAR, 415 patients (128 males and 287 females, aged 12 to 74 years) were treated with Beconase Aqueous Nasal Aerosol at a dose of 320 mcg once daily and 111 patients (44 males and 67 females, aged 12 to 67 years) were treated with placebo. Of the 415 patients treated with Beconase Aqueous Nasal Aerosol, 219 patients were treated for 52 weeks and 196 patients were treated for 30 weeks. While most adverse events were similar in type and rate between the treatment groups, epistaxis occurred more frequently in patients who received Beconase Aqueous Nasal Aerosol (45 out of 415, 11%) than in patients who received placebo (2 out of 111, 2%). Epistaxis also tended to be more severe in patients treated with Beconase Aqueous Nasal Aerosol. In 45 reports of epistaxis in patients who received Beconase Aqueous Nasal Aerosol, 27, 13, and 5 cases were of mild, moderate, and severe intensity, respectively, while the reports of epistaxis in patients who received placebo were of mild (1) and moderate (1) intensity. Seventeen patients treated with Beconase Aqueous Nasal Aerosol experienced adverse reactions that led to withdrawal from the trial compared to 3 patients treated with placebo. There were 4 nasal erosions and 1 nasal septum ulceration which occurred in patients who received Beconase Aqueous Nasal Aerosol, and no erosions or ulcerations noted in patients who received placebo. No patient experienced a nasal septum perforation during the trial.

Pediatric Patients Aged 4 to 11 Years:

The safety data described below for pediatric patients 4 to 11 years of age with seasonal or perennial allergic rhinitis are based on 3 placebo-controlled clinical trials. These trials were 2 to 12 weeks in duration, evaluated doses of beclomethasone nasal aerosol 80 mcg to 160 mcg once daily and included a total of 1360 patients with either seasonal or perennial allergic rhinitis. Of these, 668 (312 female and 356 male) received at least one dose of Beconase Aqueous Nasal Aerosol, 80 mcg once daily, 241 (116 female and 125 male) received Beconase Aqueous Nasal Aerosol 160 mcg once daily, and 451 (203 female and 248 male) received placebo. The racial distribution of patients was 73% white, 20% black, and 6% other. Based on the results from the dose ranging trial, 80 mcg once daily was chosen as the dose in pediatric patients.

Less than 1.5% of patients in the clinical trials discontinued treatment because of adverse reactions with the rate of withdrawal among patients who received Beconase Aqueous Nasal Aerosol 80 mcg once daily similar to or lower than the rate among patients who received placebo. Table 2 displays the common adverse reactions (≥ 2% and greater than placebo-treated patients). Additionally, epistaxis was reported at a rate of 4% for both Beconase Aqueous Nasal Aerosol 80 mcg once daily and placebo treated patients.

6.2 Postmarketing Experience

In addition to adverse reactions reported from clinical trials for Beconase Aqueous Nasal Aerosol, the following adverse events have been reported during postmarketing use of Beconase Aqueous Nasal Aerosol or other intranasal and inhaled formulations of Beconase Aqueous. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to Beconase Aqueous or a combination of these factors.

Beconase Aqueous Nasal Aerosol: sneezing, burning sensation

Intranasal Beconase Aqueous: Nasal septal perforation, blurred vision, glaucoma, cataracts, central serous chorioretinopathy (CSC), loss of taste and smell, and hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria have been reported following intranasal administration of Beconase Aqueous.

Inhaled Beconase Aqueous: Hypersensitivity reactions, including anaphylaxis, angioedema, rash, urticaria, and bronchospasm have been reported following the oral inhalation of Beconase Aqueous.

7 DRUG INTERACTIONS

No drug interaction studies have been performed with Beconase Aqueous Nasal Aerosol.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category C

There are no adequate and well-controlled clinical trials in pregnant women treated with Beconase Aqueous Nasal Aerosol. Beconase Aqueous was teratogenic and embryocidal in the mouse and rabbit although these effects were not observed in rats. Beconase Aqueous Nasal Aerosol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans.

Beconase Aqueous administered subcutaneously was teratogenic and embryocidal in the mouse and rabbit at doses approximately twice the maximum recommended human daily intranasal dose in adults (on a mg/m² basis at maternal doses of 0.1 and 0.025 mg/kg/day in mice and rabbits, respectively). No teratogenicity or embryocidal effects were seen in rats at approximately 460 times MRHDID (in adults on a mg/m² basis at a maternal inhalation dose of 15 mg/kg/day).

Non-teratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.

8.3 Nursing Mothers

It is not known whether Beconase Aqueous is excreted in human breast milk. However, other corticosteroids have been detected in human breast milk and thus caution should be exercised when Beconase Aqueous Nasal Aerosol is administered to a nursing mother.

8.4 Pediatric Use

The safety and effectiveness of Beconase Aqueous Nasal Aerosol in children 4 years and older have been established . The safety and effectiveness of Beconase Aqueous Nasal Aerosol in children younger than 4 years of age have not been established. Controlled pediatric clinical trials with Beconase Aqueous Nasal Aerosol included 909 children 4 to 11 years of age and 188 adolescent patients 12 to 17 years of age .

Controlled clinical trials have shown that intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA-axis function. The long-term effects of reduction in growth velocity associated with intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for "catch-up" growth following discontinuation of treatment with intranasal corticosteroids has not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids, including Beconase Aqueous Nasal Aerosol, should be monitored routinely (e.g., via stadiometry).

A 12-month, randomized, controlled clinical trial evaluated the effects of QVAR^®, an orally inhaled HFA Beconase Aqueous product, without spacer versus chlorofluorocarbon-propelled (CFC) Beconase Aqueous with large volume spacer on growth in children with asthma ages 5 to 11 years. A total of 520 patients were enrolled, of whom 394 received HFA-beclomethasone dipropionate (100 to 400 mcg/day ex-valve) and 126 received CFC-beclomethasone dipropionate (200 to 800 mcg/day ex-valve). When comparing results at month 12 to baseline, the mean growth velocity in children treated with HFA-beclomethasone dipropionate was approximately 0.5 cm/year less than that noted with children treated with CFC-beclomethasone dipropionate via large volume spacer. The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks/benefits of treatment alternatives.

The potential for Beconase Aqueous Nasal Aerosol to cause reduction in growth velocity in susceptible patients or when given at higher than recommended dosages cannot be ruled out.

8.5 Geriatric Use

Clinical trials of Beconase Aqueous Nasal Aerosol did not include sufficient numbers of subjects aged 65 years and older to determine whether they responded differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, administration to elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Chronic overdosage may result in signs/symptoms of hypercorticism . There are no data available on the effects of acute or chronic overdosage with Beconase Aqueous Nasal Aerosol.

11 DESCRIPTION

Beconase Aqueous USP, the active component of Beconase Aqueous Nasal Aerosol, 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 and the following chemical structure:

Beconase Aqueous, a di-ester of beclomethasone (a synthetic corticosteroid chemically related to dexamethasone), is a white to almost white, odorless powder with a molecular formula of C₂₈H₃₇ClO₇ and a molecular weight of 521.1. It is practically insoluble in water, very soluble in chloroform, and soluble in acetone and in dehydrated alcohol.

Beconase Aqueous Nasal Aerosol is a pressurized, nonaqueous solution in a metered-dose aerosol device intended ONLY for intranasal use. It contains a solution of Beconase Aqueous in propellant HFA-134a (1,1,1,2-tetrafluoroethane) and dehydrated ethanol. Beconase Aqueous 40 mcg Nasal Aerosol delivers 40 mcg of Beconase Aqueous from the nasal actuator and 50 mcg from the valve. Beconase Aqueous 80 mcg Nasal Aerosol delivers 80 mcg of Beconase Aqueous from the nasal actuator and 100 mcg from the valve. Each strength delivers 59 mg of solution from the valve with each actuation. Each canister of Beconase Aqueous 40 mcg or 80 mcg Nasal Aerosol, contains 8.7 g of drug and excipients and each provides 120 actuations after priming. Additionally, Beconase Aqueous 40 mcg Nasal Aerosol contains 4.9 g of drug and excipients and provides 60 actuations after priming.

Chemical structure.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Beconase Aqueous is a prodrug that is extensively converted to the active metabolite, beclomethasone-17-monopropionate. The precise mechanism through which Beconase Aqueous affects rhinitis symptoms is unknown. Corticosteroids have been shown to have multiple anti-inflammatory effects, inhibiting both inflammatory cells and the release of inflammatory mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines).

Beclomethasone-17-monopropionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor which is approximately 13 times that of dexamethasone, 6 times that of triamcinolone acetonide, 1.5 times that of budesonide and 25 times that of Beconase Aqueous. The clinical significance of these findings is unknown.

12.2 Pharmacodynamics

Adrenal Function: The effects of Beconase Aqueous Nasal Aerosol on the HPA axis were evaluated in two 6-week, randomized, double-blind, parallel-group perennial allergic rhinitis trials – one in adult and adolescent patients 12 to 45 years of age and another in children 6 to 11 years of age. In the first study with adolescent and adult patients aged 12 to 45, Beconase Aqueous Nasal Aerosol 320 mcg, once daily, was compared with both placebo nasal aerosol and a positive control (a placebo/prednisone group that received prednisone 10 mg orally once daily for the final 7 days of the treatment period). In the second study with pediatric patients aged 6 to 11, Beconase Aqueous Nasal Aerosol 80 mcg once daily was compared to placebo nasal aerosol. HPA-axis function was assessed by 24-hour serial serum cortisol levels prior to the first dose and after 6 weeks of treatment. Patients were domiciled for the 24-hour serum cortisol assessments. The change from baseline in the 24-hour serum cortisol weighted mean for Beconase Aqueous Nasal Aerosol and placebo after 6 weeks of treatment were compared.

In the HPA–axis study in patients 12 to 45 years of age, baseline geometric mean serum cortisol weighted mean values were similar in the Beconase Aqueous Nasal Aerosol 320 mcg/day and placebo treatment groups (9.04 and 8.45 mcg/dL, respectively). After 6 weeks of treatment, the geometric mean values were 8.18 and 8.01 mcg/dL, respectively, with a change from baseline in 24-hour serum cortisol weighted mean for the Beconase Aqueous Nasal Aerosol and placebo groups of 0.86 and 0.44, resulting in a difference of 0.42. The geometric mean ratio for Beconase Aqueous Nasal Aerosol 320 mcg/day to placebo was 0.96 (95% CI: 0.87, 1.06). For comparison, in the positive-control (prednisone) treatment group, the geometric mean ratio for placebo to placebo/prednisone 10 mg/day was 3.17 (95% CI: 2.68, 3.74).

In the HPA-axis study in patients 6 to 11 years of age, baseline geometric mean serum cortisol weighted mean values were similar in the Beconase Aqueous Nasal Aerosol 80 mcg/day and placebo treatment groups (5.97 and 6.47 mcg/dL, respectively). After 6 weeks of treatment the geometric mean values were 6.19 and 7.13 mcg/dL, respectively with no decrease from baseline values in both treatment groups. The geometric mean ratio for Beconase Aqueous Nasal Aerosol 80 mcg/day to placebo was 0.91 (95% CI; 0.81, 1.03).

12.3 Pharmacokinetics

Absorption

Following intranasal administration, most of the Beconase Aqueous undergoes extensive conversion to its active metabolite, beclomethasone-17-monopropionate, during absorption. Plasma concentrations of Beconase Aqueous and beclomethasone-17-monopropionate have been measured with Beconase Aqueous Nasal Aerosol in 2 adult and/or adolescent clinical trials and 1 pediatric clinical trial.

The single-dose pharmacokinetics of Beconase Aqueous Nasal Aerosol were evaluated in a randomized, open-label, 3-period, crossover trial in healthy adult volunteers. Systemic levels of beclomethasone-17-monopropionate and Beconase Aqueous after single-dose intranasal administration of Beconase Aqueous at doses of 80 and 320 mcg were compared with the systemic levels of beclomethasone-17-monopropionate and Beconase Aqueous after administration of orally inhaled Beconase Aqueous HFA at a dose of 320 mcg (QVAR^® Inhalation Aerosol). The results of this trial demonstrated that the systemic bioavailability of Beconase Aqueous Nasal Aerosol 320 mcg was approximately 27.5% (approximately 4-fold lower) of that of orally inhaled Beconase Aqueous HFA 320 mcg/day based on the plasma concentrations of beclomethasone-17-monopropionate (AUC_last: 1139.7 vs 4140.3 hr*pg/mL; GMR: 0.275; 90% CI for the GMR: 0.214, 0.354). The peak exposure to Beconase Aqueous Nasal Aerosol 320 mcg/day was approximately 19.5% (approximately 5-fold lower) of that of orally inhaled Beconase Aqueous HFA 320 mcg/day as measured by beclomethasone-17-monopropionate (C_max: 262.7 vs 1343.7 pg/mL; GMR: 0.195; 90% CI for the GMR: 0.158, 0.241).

Following repeated once-daily administration of Beconase Aqueous Nasal Aerosol, there was no accumulation or increase in plasma exposure to beclomethasone-17-monopropionate or Beconase Aqueous, most likely due to the short plasma half-life relative to the dosing frequency.

Distribution

The in vitro protein binding for beclomethasone-17-monopropionate was reported to be 94% to 96% over the concentration range of 1000 to 5000 pg/mL. The volume of distribution at steady state for Beconase Aqueous is moderate (20 L) but more extensive for beclomethasone-17-monopropionate (424 L).

Metabolism

Beconase Aqueous undergoes extensive first-pass metabolism, forming three metabolites via CYP3A4, beclomethasone-17-monopropionate, beclomethasone-21-monopropionate, and beclomethasone. Beclomethasone-17-monopropionate is the major and most active metabolite.

Elimination

The major route of elimination of inhaled Beconase Aqueous appears to be via metabolism. More than 90% of inhaled Beconase Aqueous is found as beclomethasone-17-monopropionate in the systemic circulation. The mean elimination half-life of beclomethasone-17-monopropionate is 2.8 hours. The terminal elimination half-lives of Beconase Aqueous and beclomethasone-17-monopropionate following intranasal dosing with Beconase Aqueous Nasal Aerosol (320 mcg) were approximately 0.3 hours and 4.5 hours, respectively. Irrespective of the route of administration (injection, oral, or inhalation), Beconase Aqueous and its metabolites are mainly excreted in the feces. Less than 10% of the drug and its metabolites are excreted in the urine. It is likely that intranasal Beconase Aqueous follows a similar elimination pathway.

Special Populations

Formal pharmacokinetic studies using Beconase Aqueous Nasal Aerosol were not conducted in any special populations.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenicity of Beconase Aqueous was evaluated in rats that were exposed for a total of 95 weeks: 13 weeks at inhalation doses up to 0.4 mg/kg and the remaining 82 weeks at combined oral and inhalation doses up to 2.4 mg/kg. In this trial, there was no evidence of carcinogenicity at the highest dose: approximately 70 and 120 times the maximum recommended human daily intranasal dose (MRHDID) in adults and children, respectively, on a mg/m² basis.

Beconase Aqueous did not induce gene mutation in bacterial cells or mammalian Chinese hamster ovary (CHO) cells in vitro. No significant clastogenic effect was seen in cultured CHO cells in vitro or in the mouse micronucleus test in vivo.

In rats, Beconase Aqueous caused decreased conception rates at an oral dose of 16 mg/kg (approximately 490 times the MRHDID in adults on a mg/m² basis). There was no significant effect of Beconase Aqueous on fertility in rats at oral doses of 1.6 mg/kg (approximately 50 times the MRHDID in adults on a mg/m² basis). Inhibition of the estrous cycle in dogs was observed following oral doses of 0.5 mg/kg (approximately 50 times the MRHDID in adults on a mg/m² basis). No inhibition of the estrous cycle in dogs was seen following 12 months of exposure at an estimated inhalation dose of 0.33 mg/kg (approximately 35 times the MRHDID in adults on a mg/m² basis).

14 CLINICAL STUDIES

14.1 Seasonal and Perennial Allergic Rhinitis

Adult and Adolescent Patients Aged 12 Years and Older: The efficacy and safety of Beconase Aqueous Nasal Aerosol have been evaluated in 3 randomized, double-blind, parallel-group, multicenter, placebo-controlled clinical trials of 2 to 6 weeks duration in adult and adolescent patients 12 years and older with symptoms of seasonal or perennial allergic rhinitis. The 3 clinical trials included one 2-week dose-ranging trial in patients with seasonal allergic rhinitis, one 2-week efficacy trial in patients with seasonal allergic rhinitis, and one 6-week efficacy trial in patients with perennial allergic rhinitis. The trials included a total of 1049 patients (366 males and 683 females). About 81% of patients were Caucasian and 17% African American, the mean age was approximately 38 years. Of these patients 521 received Beconase Aqueous Nasal Aerosol 320 mcg once daily administered as 2 actuations in each nostril.

Assessment of efficacy was based on the total nasal symptom score (TNSS). TNSS is calculated as the sum of the patients' scoring of the 4 individual nasal symptoms (rhinorrhea, sneezing, nasal congestion, and nasal itching) on a 0 to 3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe) as reflective (rTNSS) or instantaneous (iTNSS). rTNSS required the patients to record symptom severity over the previous 12 hours; iTNSS required the patients to record symptom severity over the previous 10 minutes. Morning and evening TNSS scores were averaged over the treatment period and the difference from placebo in the change from baseline rTNSS was the primary efficacy endpoint. The morning iTNSS reflects the TNSS at the end of the 24-hour dosing interval and is an indication of whether the effect was maintained over the 24-hour dosing interval.

Dose-Ranging Trial: The dose-ranging trial was a 2-week trial that evaluated the efficacy of 3 doses of Beconase Aqueous nasal aerosol (80, 160, and 320 mcg, once daily) in patients with seasonal allergic rhinitis. In this trial, only treatment with Beconase Aqueous nasal aerosol at the dose of 320 mcg/day resulted in statistically significant improvements compared with placebo in the primary efficacy endpoint, rTNSS ( Table 3 ).

The 320 mcg dose also demonstrated a statistically significant decrease in morning iTNSS than placebo, indicating that the effect was maintained over the 24-hour dosing interval.

Seasonal and Perennial Allergic Rhinitis Trials: In 2 randomized, double-blind, parallel-group, multicenter, placebo-controlled efficacy trials, once-daily treatment with Beconase Aqueous Nasal Aerosol for 2 weeks in patients with seasonal allergic rhinitis and for 6 weeks in patients with perennial allergic rhinitis resulted in statistically significant greater decreases from baseline in the rTNSS and morning iTNSS than placebo ( Table 4 ).

Pediatric Patients 4 to 11 Years of Age: The efficacy and safety of Beconase Aqueous Nasal Aerosol have been evaluated in 2 randomized, double-blind, parallel-group, multicenter, placebo-controlled clinical trials of 2 to 12 weeks duration in pediatric patients 4 to 11 years of age with symptoms of seasonal or perennial allergic rhinitis. The 2 clinical trials included one 2-week dose-ranging trial in patients with seasonal allergic rhinitis (6 - 11 years of age), and one 12-week efficacy trial in patients with perennial allergic rhinitis (4 - 11 years of age). The trials included a total of 1255 patients (680 males and 575 females). About 73% of patients were Caucasian and 20% African American, the mean age was approximately 8 years for one study and 9 years for the second study. Of these patients 596 received Beconase Aqueous Nasal Aerosol 80 mcg once daily administered as 1 actuation of Beconase Aqueous 40 mcg Nasal Aerosol in each nostril.

Assessment of efficacy was based on the total nasal symptom score (TNSS) as described in adult and adolescents efficacy studies.

Dose-Ranging Seasonal Allergic Rhinitis Trial: The dose-ranging trial was a 2-week trial that evaluated the efficacy of 2 doses of Beconase Aqueous nasal aerosol (80 and 160mcg, once daily) in patients with seasonal allergic rhinitis. In this trial, treatment with Beconase Aqueous nasal aerosol at the dose of 80 mcg/day resulted in statistically significant improvements compared with placebo in the primary efficacy endpoint, rTNSS ( Table 5 ).

The 80 mcg daily dose also demonstrated a statistically significant decrease in morning iTNSS than placebo, indicating that the effect was maintained over the 24-hour dosing interval. Based on the results from the dose ranging trial, 80 mcg once daily was chosen as the dose for pediatric patients 4-11 years of age.

Perennial Allergic Rhinitis Trial: In a randomized, double-blind, parallel-group, multicenter, placebo-controlled efficacy trial, treatment with Beconase Aqueous Nasal Aerosol 80 mcg once daily in patients with perennial allergic rhinitis resulted in statistically significant greater decreases from baseline in the rTNSS (the primary endpoint) and iTNSS than placebo over the first six weeks of treatment ( Table 6 ).

FAS=full analysis set

For pediatric patients 4-11 years of age, improvements in average patient-reported rTNSS and iTNSS were also significantly greater in Beconase Aqueous Nasal Aerosol 80 mcg per day treated patients compared with placebo.

16 HOW SUPPLIED/STORAGE AND HANDLING

Beconase Aqueous Nasal Aerosol is supplied in 2 strengths and supplied as a pressurized aluminum canister inserted into a blue and white plastic nasal actuator with a built-in dose counter and white dust cap, as follows:

Beconase Aqueous 40 mcg Nasal Aerosol contains 8.7 g of drug and excipients and provides 120 actuations (NDC 59310-206-12) and for the 60-actuation product, 4.9 g of drug and excipients (NDC 59310-206-06). Each actuation delivers 40 mcg of Beconase Aqueous from the nasal actuator and 50 mcg from the valve.

Beconase Aqueous 80 mcg Nasal Aerosol contains 8.7 g of drug and excipients and provides 120 actuations (NDC 59310-210-12). Each actuation delivers 80 mcg of Beconase Aqueous from the nasal actuator and 100 mcg from the valve.

Each canister of Beconase Aqueous Nasal Aerosol has a built-in spray counter, which starts at 124 and counts down each time a spray is released for the 120 actuation product and 64 for the 60 actuation product. After the 4 initial priming sprays, the spray counter should read 120 sprays or 60 sprays for the respective products. The correct amount of medication in each intranasal dose cannot be ensured after the counter reads 0; therefore, the device should be discarded when the counter reads 0.

Do not remove the Beconase Aqueous Nasal Aerosol canister from the actuator. The Beconase Aqueous Nasal Aerosol canister should only be used with the Beconase Aqueous Nasal Aerosol actuator and the actuator should not be used with any other drug product.

CONTENTS UNDER PRESSURE

Do not puncture. Do not store near heat or open flame. Do not expose to temperatures higher than 49°C (120°F) as this may cause bursting of the canister. Never throw the device into a fire or an incinerator.

Store at 25°C (77°F); excursions are permitted between 15° and 30°C (59° and 86°F).

Keep out of reach of children.

17 PATIENT COUNSELING INFORMATION

17.1 Local Nasal Effects

Inform patients that treatment with Beconase Aqueous Nasal Aerosol may lead to adverse reactions, including epistaxis, nasal ulceration, and nasal discomfort. Candida infection may also occur with treatment with Beconase Aqueous Nasal Aerosol. In addition, nasal Beconase Aqueous products are known to be associated with nasal septal perforation and impaired wound healing. Patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should not use Beconase Aqueous Nasal Aerosol until healing has occurred .

17.2 Eye Disorders

Inform patients that blurred vision, glaucoma and cataracts are associated with nasal and inhaled corticosteroid use. Patients should inform their health care providers if a change in vision is noted while using Beconase Aqueous Nasal Aerosol .

17.3 Hypersensitivity Reactions Including Anaphylaxis

Hypersensitivity reactions including anaphylaxis, angioedema, urticaria, and rash have been reported following administration of Beconase Aqueous nasally administered and inhalationally administered products. Angioedema, urticaria, and rash have been reported following administration of Beconase Aqueous Nasal Aerosol. If any such reactions occur, patients should discontinue use of Beconase Aqueous Nasal Aerosol .

17.4 Immunosuppression

Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. Patients should be informed of potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex .

17.5 Use Daily for Best Effect

Patients should use Beconase Aqueous Nasal Aerosol on a regular, once-daily basis since its effectiveness depends on its regular use. Beconase Aqueous Nasal Aerosol may not have an immediate effect on rhinitis symptoms. The patient should not increase the prescribed dosage but should contact their physician if symptoms do not improve or if the condition worsens.

17.6 Keep Spray Out of Eyes or Mouth

Patients should be informed to avoid spraying Beconase Aqueous Nasal Aerosol in their eyes or mouth.

Teva Respiratory, LLC

Frazer, PA 19355 USA

©2017, Teva Respiratory, LLC. All rights reserved.

Beconase Aqueous^® is a registered trademark of Teva Respiratory, LLC.

Manufactured for Teva Respiratory, LLC

Frazer, PA 19355

By: 3M Drug Delivery Systems

Northridge, CA 91324

United States Patent Nos. 7,780,038

PE3533 Rev. 07/2017

Teva Respiratory logo

PLEASE SEE REVERSE SIDE FOR INSTRUCTIONS FOR USE.

INSTRUCTIONS FOR USE

Beconase Aqueous (kyoo nay' zel) 80 mcg

(beclomethasone dipropionate)

Nasal Aerosol

Read these Instructions for Use for Beconase Aqueous Nasal Aerosol before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment.

Note: For Use in the Nose Only.

• Do not spray Beconase Aqueous Nasal Aerosol in your eyes, mouth or directly onto your nasal septum (the wall between your 2 nostrils).

The parts of your Beconase Aqueous Nasal Aerosol

The Beconase Aqueous Nasal Aerosol device comes as a canister that fits into a nasal actuator with a built-in spray counter and protective dust cap. .

• Do not use the Beconase Aqueous Nasal Aerosol actuator with a canister of medicine from any other inhaler.
• Do not use the Beconase Aqueous Nasal Aerosol canister with an actuator from any other inhaler.
• Do not remove the Beconase Aqueous Nasal Aerosol canister from the actuator.

Priming your Beconase Aqueous Nasal Aerosol for Use

Your Beconase Aqueous Nasal Aerosol device must be primed before you use it for the first time or if it has not been used for more than 7 days in a row.

• Remove your Beconase Aqueous Nasal Aerosol device from its package.
• Remove the protective dust cap from the device by pulling it straight off.
• Hold the nasal actuator upright between your thumb and forefinger (index finger). The canister should be on top and the white nasal actuator tip on bottom .

• If you have never used your Beconase Aqueous Nasal Aerosol device before, spray it 4 times into the air, away from your eyes and face, by pressing down fully on the top of the canister 4 times .

• After the first time you prime your Beconase Aqueous Nasal Aerosol device, the spray counter should read 120 .

• Your Beconase Aqueous Nasal Aerosol device is now ready to use.
• Do not prime your Beconase Aqueous Nasal Aerosol device every day.
• If you have used your Beconase Aqueous Nasal Aerosol device before, but it has not been used in more than 7 days, it must be reprimed. To reprime your Beconase Aqueous Nasal Aerosol device, spray 2 times into the air, away from your eyes and face, by pressing down fully on the top of the canister 2 times. Your Beconase Aqueous Nasal Aerosol device is now ready to use.

Using Your Beconase Aqueous Nasal Aerosol Device

Step 1: Blow your nose to clear your nostrils.

Step 2: Remove the protective dust cap from your Beconase Aqueous Nasal Aerosol device by pulling it straight off.

Step 3: Inspect the nasal actuator tip to make sure it is clear of foreign objects.

Step 4: Hold your Beconase Aqueous Nasal Aerosol device upright and insert the nasal actuator tip into one nostril .

Step 5: Point the Beconase Aqueous Nasal Aerosol device slightly away from the wall between your nostrils (nasal septum) while holding your other nostril closed .

Step 6: Hold your breath and press down firmly and completely on the canister to release 1 spray . Continue to hold your breath for 5 seconds after releasing the spray and then breathe out slowly through your mouth. Take the Beconase Aqueous Nasal Aerosol device out of your nostril.

Step 7: Repeat steps 3-6 for the second spray in the same nostril.

Step 8: Repeat steps 3-7 for your other nostril.

Step 9: You should not blow your nose for the next 15 minutes.

Note: The spray counter will count down each time there is a spray released from your Beconase Aqueous Nasal Aerosol device.

Step 10: Clean and store your device. See "Cleaning Your Beconase Aqueous Nasal Aerosol device."

Cleaning Your Beconase Aqueous Nasal Aerosol device

• Wipe the nasal actuator tip with a clean, dry tissue or cloth .
• Do not wash or put any part of the Beconase Aqueous Nasal Aerosol canister or actuator in water.
• Replace the protective dust cap.
• Keep your device clean and dry at all times.

How to know when to stop using your Beconase Aqueous Aerosol device

• The Beconase Aqueous Nasal Aerosol device has a spray counter, which is there to let you know how many sprays of medicine you have left.
• Do not use your Beconase Aqueous Nasal Aerosol device when 0 is shown in the spray counter window .

• Throw away your Beconase Aqueous Nasal Aerosol device when the spray counter reaches 0.
• Do not throw your Beconase Aqueous Nasal Aerosol canister into a fire or an incinerator.
• Talk with your healthcare provider before your Beconase Aqueous Nasal Aerosol medicine runs out to see if you should get a refill.

Manufactured for: Teva Respiratory, LLC

Frazer, PA 19355

By: 3M Drug Delivery Systems

Northridge, CA 91324

©2017 Teva Respiratory, LLC

All rights reserved.

Beconase Aqueous is a registered trademark of Teva Respiratory, LLC

Rev. 07/2017 PE 3534

This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.

Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I

Beconase Aqueous 80 mcg (beclomethasone dipropionate) Nasal Aerosol, 120 Metered Sprays Carton Text

NDC 59310-210-12

Beconase Aqueous

(beclomethasone

diproprionate)

Nasal Aerosol

80 mcg per spray

For Intranasal Use with

Beconase Aqueous Actuator Only

Rx only

120 Metered Sprays

8.7g Net Contents

TEVA

Beconase Aqueous 80 mcg (beclomethasone dipropionate) Nasal Aerosol, 120 Metered Sprays Carton

Beconase Aqueous pharmaceutical active ingredients containing related brand and generic drugs:

• Beclomethasone Dipropionate

Beconase Aqueous available forms, composition, doses:

• Spray; Nasal; Beclomethasone Dipropionate 50 mcg / dose

Beconase Aqueous destination | category:

• Human:
• Adrenals
• Anti-inflammatory agents
• Antiasthmatic and COPD preparations
• Corticosteroids
• Nasal decongestants and other nasal preparations
• Topical corticosteroids

Beconase Aqueous Anatomical Therapeutic Chemical codes:

• D07AC15 - Beclometasone
• R01AD01 - Beclometasone
• R03BA01 - Beclometasone

Beconase Aqueous pharmaceutical companies:

• Allen & Hanburys
• Firma Chun Cheong
• GlaxoSmithKline
• Zuellig Pharma

References

1. Dailymed."QNASL (BECLOMETHASONE DIPROPIONATE) AEROSOL, METERED [TEVA RESPIRATORY, LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. Dailymed."BECLOMETHASONE DIPROPIONATE MONOHYDRATE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
3. "BECLOMETHASONE DIPROPIONATE". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Depending on the reaction of the Beconase Aqueous after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Beconase Aqueous not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology