Rhinocort

Indications : Asthma; Rhinitis, perennial allergic; Rhinitis, perennial nonallergic; Rhinitis, seasonal allergic

Pregnancy Category C

FDA Class 1S (“Standard Review”)

FDA Approved 1994 Feb

DRUG CLASS : Corticosteroids

BRAND NAMES : Budamax (Australia); Budecort *; Budecort Nasal (Philippines); Budeflam (US); Budenofalk (Germany); Budeson 3 (Israel); Budicort Respules (Israel); Butacort (New-Zealand); Eltair (New-Zealand); Pulmicort (US); Pulmicort Nasal Turbohaler (Korea); Rhinocort (US);
(International brand names outside U.S. in italics) * Indicates foreign drugs without region specification at time of publication.

DESCRIPTION :

Budesonide, the active component of Rhinocort nasal inhaler, Rhinocort Aqua nasal spray, and Pulmicort Turbuhaler is an anti-inflammatory, synthetic corticosteroid. It is designated chemically as (RS)-11beta,16alpha, 17,21-Tetrahydroxy-pregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butraldehyde. Budesonide is provided as the mixture of two epimers (22R and 22S). The empirical formula of Budesonide is C25H34O6 and its molecular weight is 430.5.

Budesonide is a white to off-white tasteless, odorless powder that is practically insoluble in water and in heptane, sparingly soluble in ethanol, and freely soluble in chloroform.

Rhinocort Nasal Inhaler : A metered-dose pressurized aerosol unit containing a suspension of micronized Budesonide in a mixture of propellants, (dichlorodifluoromethane, trichloromonofluoromethane, and dichlorotetrafluoroethane) and sorbitan trioleate. Each actuation releases 50 mug Budesonide from the valve and delivers approximately 32 mug Budesonide from the nasal adapter (dose to patient). Throughout the package insert 32 mug per actuation is used to calculate the dose administered. One canister provides at least 200 metered doses.

Its partition coefficient between octanol and water at pH 7.4 is 1.6 × 103.

Rhinocort Aqua Nasal Spray : Rhinocort Aqua is an unscented, metered-dose, manual-pump spray formulation containing a micronized suspension of Budesonide in an aqueous medium. Microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose anhydrous, polysorbate 80, disodium edetate, potassium sorbate, and purified water are contained in this medium; hydrochloric acid is added to adjust the pH to a target of 4.5.

Rhinocort Aqua nasal spray is available in two dose strengths which deliver 32 mug and 64 mug, respectively, of Budesonide per spray. Each Bottle of Rhinocort Aqua Nasal Spray 32 mug: Contains 60 or 120 metered sprays after initial priming. Each Bottle of Rhinocort Aqua Nasal Spray 64 mug: Contains 120 metered sprays after initial priming.

Prior to initial use, the container must be shaken gently and the pump must be primed by actuating 8 times. If used daily, the pump does not need to be reprimed. If not used for two consecutive days, reprime with one spray or until a fine spray appears. If not used for more than 14 days, rinse the applicator and reprime with two sprays or until a fine spray appears.

Its partition coefficient between octanol and water at pH 5 is 1.6 × 103.

Pulmicort Turbuhaler: Pulmicort Turbuhaler is an inhalation-driven multi-dose dry powder inhaler which contains only micronized Budesonide. Each actuation of Pulmicort Turbuhaler provides 200 mug Budesonide per metered dose, which delivers approximately 160 mug Budesonide from the mouthpiece (based on in vitro testing at 60 L/min for 2 sec). The amount of drug delivered to the lung will depend on patient factors such as inspiratory flow (see PATIENT PACKAGE INSERT). In adult patients with asthma (mean FEV1 2.9 L [0.8 – 5.1 L]) mean peak inspiratory flow (PIF) through Pulmicort Turbuhaler was 78 (40-111) L/min. Similar results (mean PIF 82 [43-125] L/min) were obtained in asthmatic children (6-15 years, mean FEV1 2.1 L [0.9 – 5.4 L]).

Its partition coefficient between octanol and water at pH 7.4 is 1.6 × 103.

CLINICAL PHARMACOLOGY :

Budesonide is a synthetic corticosteroid having a potent glucocorticoid and weak mineralocorticoid activity. In standard in vitro and animal models, Budesonide has an approximately 200-fold higher affinity for the glucocorticoid receptor and a 1000-fold higher topical anti-inflammatory potency than cortisol (rat croton oil ear edema assay). As a measure of systemic activity, Budesonide is 40 times more potent than cortisol when administered subcutaneously and 25 times more potent when administered orally in the rat thymus involution assay. In glucosteroid receptor affinity studies, the 22R form was twice as active as the 22S epimer.

The precise mechanism of corticosteroid actions in seasonal and perennial allergic and nonallergic rhinitis is not known. Corticosteroids have been shown to have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes and cytokines) involved in allergic- and nonallergic/irritant-mediated inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.

Corticosteroids affect the delayed (6 hour) response to an allergen challenge more than the histamine-associated immediate response (20 minute). The clinical significance of these findings is unknown.

Additional Information for Budesonide Inhalation Powder : Studies in asthmatic patients have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects over a wide range of doses from Budesonide inhalation powder. This is explained by a combination of a relatively high local anti-inflammatory effect, extensive first pass hepatic degradation of orally absorbed drug (85-95%), and the low potency of formed metabolites (see Pharmacokinetics).

Pharmacokinetics

The pharmacokinetics of Budesonide have been studied following nasal, oral, and intravenous administration. Budesonide is relatively well absorbed after both inhalation and oral administration, and is rapidly metabolized into metabolites with low corticosteroid potency. The activity of Budesonide nasal spray, nasal inhaler, and oral inhalation powder is due to the parent drug, Budesonide. In glucocorticoid receptor affinity studies, the 22R form was two times as active as the 22S epimer. In vitro studies indicated that the two forms of Budesonide do not interconvert. The 22R form was preferentially cleared by the liver with systemic clearance of 1.4 L/min vs. 1.0 L/min for the 22S form. The terminal half-life, 2-3 hours, was the same for both epimers and was independent of dose.

Additional Information for Budesonide Inhalation Powder: In asthmatic patients, Budesonide showed a linear increase in AUC and Cmax with increasing dose after both a single dose and repeated dosing from Budesonide oral inhalation powder.

Absorption

Budesonide Nasal Inhaler : The pharmacokinetic studies were perfomed with doses higher than those used clinically because at clinical doses the resulting plasma levels are below the limits of detection. The results are shown in TABLE 1.

TABLE 1
Mean* (Range)
Route of Administration
Tmax (hr)
Cmax (nmol/L)
Systemic Availability
VD (L)
Clearance (L/min)
Nasal Inhaler (N=9)
0.6 (0.3-2)
0.52 (0.24-0.88)
21 [16-27]
Oral Capsule (N=11)
1.0[0.5-2]
0.33[0.19-0.50]
12[8-20]
IV
100
201[102-275]
1.2[0.8-1.5]
* Mean of the two epimers.
Dose normalized to a 256 mug dose.
% of delivered dose.

Only about 20% of an intranasal dose from the Budesonide nasal inhaler reaches the systemic circulation.

While Budesonide is well absorbed from the GI tract, the oral bioavailability of Budesonide is low (10%) primarily due to extensive first pass metabolism in the liver. After reaching the systemic circulation, plasma levels decline in a log linear manner with an apparent elimination half-life of approximately 2 hours.

Budesonide has a volume of distribution of approximately 200 L and is 88% protein bound in the plasma.

Budesonide Nasal Spray: Following intranasal administration of Budesonide, the mean peak plasma concentration occurs at approximately 0.7 hours. Compared to an intravenous dose, approximately 34% of the delivered intranasal dose reaches the systemic circulation, most of which is absorbed through the nasal mucosa. While Budesonide is well absorbed from the GI tract, the oral bioavailability of Budesonide is low (10%) primarily due to extensive first pass metabolism in the liver.

Budesonide Inhalation Powder: After oral administration of Budesonide, peak plasma concentration was achieved in about 1-2 hours and the absolute systemic availability was 6-13%. In contrast, most of Budesonide delivered to the lungs is systemically absorbed. In healthy subjects, 34% of the metered dose was deposited in the lungs (as assessed by plasma concentration method) with an absolute systemic availability of 39% of the metered dose. Pharmacokinetics of Budesonide do not differ significantly in healthy volunteers and asthmatic patients. Peak plasma concentrations of Budesonide occurred within 30 minutes of inhalation from Budesonide inhalation powder.

Distribution

Budesonide has a volume of distribution of approximately 2-3 L/kg. The volume of distribution for the 22R epimer is almost twice that of the 22S epimer. Protein binding of Budesonide in vitro is constant (85-90%) over a concentration range (1-100 nmol/L) which exceeded that achieved after administration of recommended doses. It was 85-90% bound to plasma proteins. Budesonide shows little to no binding to glucocorticosteroid binding globulin. It rapidly equilibrates with red blood cells in a concentration independent manner with a blood/plasma ratio of about 0.8.

Metabolism

Budesonide is rapidly and extensively metabolized in humans by the liver. Two major metabolites (16alpha-hydroxyprednisolone and 6beta-hydroxyBudesonide) are formed via cytochrome P450 3A isoenzyme-catalyzed biotransformation. Known metabolic inhibitors of cytochrome P450 3A (e.g., ketoconazole), or significant hepatic impairment, may increase the systemic exposure of unmetabolized Budesonide (see WARNINGS and PRECAUTIONS). In vitro studies on the binding of the two primary metabolites to the corticosteroid receptor indicate that they have less than 1% of the affinity for the receptor as the parent compound Budesonide. In vitro studies have evaluated sites of metabolism and showed negligible metabolism in skin, lung, and serum. No qualitative difference between the in vitro and in vivo metabolic patterns could be detected.

Elimination

Budesonide is excreted in the urine and feces in the form of metabolites. After intranasal administration of a radio labeled dose, 2/3 of the radioactivity was found in the urine and the remainder in the feces. The main metabolites of Budesonide in the 0-24 hour urine sample following IV administration are 16alpha-hydroxyprednisolone (24%) and 6beta-hydroxyBudesonide (5%). An additional 34% of the radioactivity recovered in the urine was identified as conjugates. Approximately 60% of an intravenous radiolabelled dose was recovered in the urine. No unchanged Budesonide was detected in the urine.

The 22R form was preferentially cleared with clearance value of 1.4 L/min vs. 1.0 L/min for the 22S form. The terminal half-life, 2 to 3 hours, was similar for both epimers and it appeared to be independent of dose.

These results regarding the metabolic fate of Budesonide parallel results obtained inin vitro metabolic studies using human liver homogenates.

Special Populations
Geriatric

No specific pharmacokinetic study has been undertaken in subjects >65 years of age.

Pediatric

Budesonide Nasal Spray and Inhaler : After administration of Budesonide, the time to reach peak drug concentrations and plasma half-life were similar in children and in adults. Children had plasma concentrations approximately twice those observed in adults due primarily to differences in weight between children and adults.

Budesonide Inhalation Powder : Following intravenous dosing in pediatric patients age 10-14 years, plasma half-life was shorter than in adults (1.5 hrs vs 2.0 hrs in adults). In the same population following inhalation of Budesonide via a pressurized metered-dose inhaler, absolute systemic availability was similar to that in adults.

Gender

No specific pharmacokinetic study has been conducted to evaluate the effect of gender on Budesonide pharmacokinetics. However, following administration of 400 mug Budesonide to 7 male and 8 female volunteers in a pharmacokinetic study, no major gender differences in the pharmacokinetic parameters were found.

Race

No specific study has been undertaken to evaluate the effect of race on Budesonide pharmacokinetics.

Renal Insufficiency

The pharmacokinetics of Budesonide have not been investigated in patients with renal insufficiency.

Hepatic Insufficiency

Reduced liver function may affect the elimination of corticosteroids. The pharmacokinetics of orally administered Budesonide were affected by compromised liver function as evidenced by a doubled systemic availability. The intravenous pharmacokinetics of Budesonide were, however, similar in cirrhotic patients and in healthy subjects. The relevance of these findings to intranasally administered Budesonide have not been established.

Drug-drug Interactions

Ketoconazole, a potent inhibitor of cytochrome P450 3A, the main metabolic enzyme for corticosteroids, increased plasma levels of orally ingested Budesonide. At recommended doses, cimetidine had a slight but clinically insignificant effects on the pharmacokinetics of oral Budesonide.

Pharmacodynamics

A 3 week clinical study in seasonal rhinitis, comparing Budesonide nasal inhaler and orally ingested Budesonide with placebo in 98 patients with allergic rhinitis due to birch pollen, demonstrated that the therapeutic effect of Budesonide nasal spray and nasal inhaler can be attributed to the topical effects of Budesonide. Intranasally, 128 mug of Budesonide applied twice daily (55 mug systemically absorbed/day) provided clinically and statistically significant evidence of efficacy, whereas 250 mug of Budesonide ingested twice a day as a capsule (65 mug systemically absorbed/day) was no different from placebo in reducing nasal symptoms.

Budesonide Nasal Inhaler

The effect of Budesonide nasal inhaler at a dosage of 2 sprays in each nostril morning and evening (total daily dose of 256 mug) on hypothalamic-pituitary-adrenal (HPA) axis function has been evaluated in 275 adults and 61 children following short-term use (<2 months) and in 113 adults and 116 children following longer use (6-48 months). Early morning plasma cortisol and the short cosyntropin stimulation test (30-60 minutes) were the most commonly performed assessments of HPA function. Twenty-four hour urinary cortisol levels were determined in 50 adults (short term) and 96 children (long term). There were no statistically significant changes from baseline measurements in early morning plasma cortisol or 24-hour urinary cortisol excretion or in response to cosyntropin.

In a crossover trial using single doses of 200, 400 and 800 mug of an aqueous formulation of Budesonide administered intranasally at 10 P.M., a dose-dependent decrease in urinary cortisol excretion was found between 10 P.M. and 8 A.M. the following morning. The same study has not been performed with Budesonide nasal inhaler. However, in a study using the Budesonide nasal inhaler administered at 10 P.M., doses four (1024 mug) and eight (2048 mug) times higher than the recommended daily dose (256 mug) were followed by a significant decrease in plasma cortisol levels at 8 A.M. the following morning (17% and 22%, respectively).

Budesonide Nasal Spray

The effects of Budesonide nasal spray on adrenal function have been evaluated in several clinical trials. In a four-week clinical trial, 61 adult patients who received 256 mug daily of Budesonide nasal spray demonstrated no significant differences from patients receiving placebo in plasma cortisol levels measured before and 60 minutes after 0.25 mg intramuscular cosyntropin. There were no consistent differences in 24-hour urinary cortisol measurements in patients receiving up to 400 mug daily. Similar results were seen in a study of 150 children and adolescents aged 6 to 17 with perennial rhinitis who were treated with 256 mug daily for up to 12 months.

After treatment with the recommended maximal daily dose of Budesonide nasal spray (256 mug) for 7 days, there was a small, but statistically significant decrease in the area under the plasma cortisol-time curve over 24 hours (AUC0-24hr) in healthy adult volunteers.

A dose-related suppression of 24-hour urinary cortisol excretion was observed after administration of Budesonide nasal spray doses ranging from 100-800 mug daily for up to 4 days in 78 healthy adult volunteers. The clinical relevance of these results is unknown.

Budesonide Inhalation Powder

To confirm that systemic absorption is not a significant factor in the clinical efficacy of inhaled Budesonide, a clinical study in patients with asthma was performed comparing 400 mug Budesonide administered via a pressurized metered dose inhaler with a tube spacer to 1400 mug of oral Budesonide and placebo. The study demonstrated the efficacy of inhaled Budesonide but not orally ingested Budesonide despite comparable systemic levels. Thus, the therapeutic effect of conventional doses of orally inhaled Budesonide are largely explained by its direct action on the respiratory tract.

Generally, Budesonide has a relatively rapid onset of action for an inhaled corticosteroid. Improvement in asthma control following inhalation of Budesonide inhalation powder can occur within 24 hours of beginning treatment although maximum benefit may not be achieved for 1 to 2 weeks, or longer.

Budesonide inhalation powder has been shown to decrease airway reactivity to various challenge models, including histamine, methacholine, sodium metabisulfite, and adenosine monophosphate in hyperreactive patients. The clinical relevance of these models is not certain.

Pretreatment with Budesonide inhalation powder 1600 mug daily (800 mug twice daily) for 2 weeks reduced the acute (early-phase reaction) and delayed (late-phase reaction) decrease in FEV1 following inhaled allergen challenge.

The effects of Budesonide inhalation powder on the hypothalamic-pituitary-adrenal (HPA) axis were studied in 905 adults and 404 pediatric patients with asthma. For most patients, the ability to increase cortisol production in response to stress, as assessed by cosyntropin (ACTH) stimulation test, remained intact with Budesonide inhalation powder treatment at recommended doses. For adult patients treated with 100, 200, 400, or 800 mug twice daily for 12 weeks, 4%, 2%, 6%, and 13% respectively, had an abnormal stimulated cortisol response (peak cortisol <14.5 mug/dl assessed by liquid chromatography following short-cosyntropin test) as compared to 8% of patients treated with placebo. Similar results were obtained in pediatric patients. In another study in adults, doses of 400, 800, and 1600 mug Budesonide twice daily via Budesonide inhalation powder for 6 weeks were examined; 1600 mug twice daily (twice the maximum recommended dose) resulted in a 27% reduction in stimulated cortisol (6-hour ACTH infusion) while 10 mg prednisone resulted in a 35% reduction. In this study, no patient on Budesonide inhalation powder at doses of 400 and 800 mug twice daily met the criterion for an abnormal stimulated cortisol response (peak cortisol <14.5 mug/dl assessed by liquid chromatography) following ACTH infusion. An open-label, long-term follow-up of 1133 patients for up to 52 weeks confirmed the minimal effect on the HPA axis (both basal and stimulated plasma cortisol) of Budesonide inhalation powder when administered at recommended doses. In patients who had previously been oral steroid-dependent, use of Budesonide inhalation powder in recommended doses was associated with higher stimulated cortisol response compared to baseline following 1 year of therapy.

The administration of Budesonide via Budesonide inhalation powder in doses up to 800 mug/day (mean daily dose 445 mug/day) or via a pressurized metered-dose inhaler in doses up to 1200 mug/day (mean daily dose 620 mug/day) to 216 pediatric patients (age 3-11 years) for 2-6 years had no significant effect on statural growth compared with non-corticosteroid therapy in 62 matched control patients. However, the long-term effect of Budesonide inhalation powder on growth is not fully known.

CLINICAL STUDIES :

Budesonide Nasal Inhaler

The prophylactic and therapeutic efficacy of Budesonide nasal inhaler has been evaluated in 20 controlled clinical trials of seasonal or perennial rhinitis. The number of patients treated with Budesonide in these studies was 50 male and 33 female patients ages 6-12 years old, 77 males and 62 females ages 13-18 years old, 185 males and 246 females ages 19-64 and 1 male and 2 females over 64. The patients were predominantly caucasian.

Double-blind clinical trials of 2-4 weeks duration have shown that, compared with placebo, Budesonide nasal inhaler 128 mug bid (2 sprays in each nostril morning and evening) or 256 mug qd (4 sprays in each nostril in the morning) provides statistically significant relief of nasal symptoms such as blockage, rhinorrhea, itching, and sneezing in adults and children with seasonal allergic rhinitis or perennial allergic rhinitis. Similar improvement has also been demonstrated in adults with nonallergic perennial rhinitis.

The therapeutic effect of Budesonide nasal inhaler compared with placebo has been demonstrated by rhinoscopic examinations, in children and adults with seasonal or perennial allergic rhinitis and adults with nonallergic perennial rhinitis. Biopsies of the nasal mucosa of 50 adult patients after 12 months of treatment and of 10 patients after 3-5 years of therapy showed no histopathological evidence of adverse effects. The clinical significance of either of these findings is unknown.

Budesonide Nasal Spray

The therapeutic efficacy of Budesonide nasal spray has been evaluated in placebo-controlled clinical trials of seasonal and perennial allergic rhinitis of 3-6 weeks duration.

The number of patients treated with Budesonide nasal spray in these studies was 90 males and 51 females aged 6-12 years and 691 males and 694 females 12 years and above. The patients were predominantly Caucasian.

Overall, the results of these clinical trials showed that Budesonide nasal spray administered once daily provides statistically significant reduction in the severity of nasal symptoms of seasonal and perennial allergic rhinitis including runny nose, sneezing, and nasal congestion.

In some studies, improvement versus placebo has been shown to occur within 24 hours of initiating treatment with Budesonide nasal spray. Maximum benefit is generally not achieved until 2 weeks after initiation of treatment.

Budesonide Inhalation Powder

The therapeutic efficacy of Budesonide inhalation powder has been evaluated in controlled clinical trials involving more than 1300 patients (6 years and older) with asthma of varying disease duration (<1 year to >20 years) and severity.

Double-blind, parallel, placebo-controlled clinical trials of 12 weeks duration and longer have shown that, compared with placebo, Budesonide inhalation powder significantly improved lung function (measured by PEF and FEV1), significantly decreased morning and evening symptoms of asthma, and significantly reduced the need for as needed inhaled beta2-agonist use at doses of 400-1600 mug per day (200-800 mug twice daily) in adults and 400-800 mug per day (200-400 mug twice daily) in pediatric patients 6 years of age and older.

Improved lung function (morning PEF) was observed within 24 hours of initiating treatment in both adult and pediatric patients 6 years of age and older, although maximum benefit was not achieved for 1-2 weeks, or longer, after starting treatment. Improved lung function was maintained throughout the 12 weeks of the double-blind portion of the trials.

Patients Not Receiving Corticosteroid Therapy : In a 12-week clinical trial in 273 patients with mild to moderate asthma (mean baseline FEV1 2.27 L) who were not well controlled by bronchodilators alone, Budesonide inhalation powder was evaluated at doses of 200 mug twice daily and 400 mug twice daily versus placebo. Pulmonary function improved significantly on both doses of Budesonide inhalation powder compared with placebo.

In a 12-month controlled trial in 75 patients not previously receiving corticosteroids, Budesonide inhalation powder at 200 mug twice daily resulted in improved lung function (measured by PEF) and reduced bronchial hyperreactivity compared to placebo.

Patients Previously Maintained on Inhaled Corticosteroids : The safety and efficacy of Budesonide inhalation powder was also evaluated in adult and pediatric patients (age 6-18 years) previously maintained on inhaled corticosteroids (adults: N=473, mean baseline FEV1 2.04 L, baseline doses of beclomethasone dipropionate 126-1008 mug/day; pediatrics: N=404, mean baseline FEV1 2.09 L, baseline doses of beclomethasone dipropionate 126-672 mug/day or triamcinolone acetonide 300-1800 mug/day). Pulmonary function improved significantly with all doses of Budesonide inhalation powder compared to placebo in both trials.

Patients Receiving Budesonide Inhalation Powder Once Daily : The efficacy and safety of once-daily administration of Budesonide inhalation powder 200 mug and 400 mug and placebo were also evaluated in 309 adult asthmatic patients (mean baseline FEV1 2.7 L) in an 18-week study. Compared with placebo, patients receiving Budesonide 200 or 400 mug once daily showed significantly better asthma stability as assessed by PEF and FEV1 over an initial 6-week treatment period, which was maintained with a 200 mug daily dose over the subsequent 12 weeks. Although the study population included both patients previously treated with inhaled corticosteroids, as well as patients not previously receiving corticosteroid therapy, the results showed that once-daily dosing was most clearly effective for those patients previously maintained on orally inhaled corticosteroids (see DOSAGE AND ADMINISTRATION).

Patients Previously Maintained on Oral Corticosteroids : In a clinical trial in 159 severe asthmatic patients requiring chronic oral prednisone therapy (mean baseline prednisone dose 19.3 mg/day) Budesonide inhalation powder at doses of 400 mug twice daily and 800 mug twice daily was compared to placebo over a 20-week period. Approximately two-thirds (68% on 400 mug twice daily and 64% on 800 mug twice daily) of Budesonide inhalation powder-treated patients were able to achieve sustained (at least 2 weeks) oral corticosteroid cessation (compared with 8% of placebo-treated patients) and improved asthma control. The average oral corticosteroid dose was reduced by 83% on 400 mug twice daily and 79% on 800 mug twice daily for Budesonide inhalation powder-treated patients vs. 27% for placebo. Additionally, 58 out of 64 patients (91%) who completely eliminated oral corticosteroids during the double-blind phase of the trial remained off oral corticosteroids for an additional 12 months while receiving Budesonide inhalation powder.

INDICATIONS AND USAGE :

Budesonide Nasal Inhaler : Budesonide nasal inhaler is indicated for the management of symptoms of seasonal or perennial allergic rhinitis in adults and children and nonallergic perennial rhinitis in adults. Budesonide nasal inhaler is not recommended for treatment of nonallergic rhinitis in children because adequate numbers of such children have not been studied.

Budesonide Nasal Spray : Budesonide nasal spray is indicated for the management of nasal symptoms of seasonal or perennial allergic rhinitis in adults and children 6 years of age and older.

Budesonide Inhalation Powder : Budesonide inhalation powder is indicated for the maintenance treatment of asthma as prophylactic therapy in adult and pediatric patients 6 years of age or older. It is also indicated for patients requiring oral corticosteroid therapy for asthma. Many of those patients may be able to reduce or eliminate their requirement for oral corticosteroids over time.

Budesonide inhalation powder is NOT indicated for the relief of acute bronchospasm.

CONTRAINDICATIONS:

Hypersensitivity to any of the ingredients in these preparations contraindicates its use.

Budesonide Inhalation Powder : Budesonide inhalation powder is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.

WARNINGS :

The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency, and in addition some patients may experience symptoms of 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 those patients who have asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, too rapid a decrease in systemic glucocorticosteroids may cause a severe exacerbation of their symptoms.

Patients who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in non-immune children or adults on immunosuppressant doses of corticosteroids. In such children or adults, who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See respective prescribing information.) If chicken pox develops, treatment with antiviral agents may be considered.

Additional Information for Budesonide Nasal Inhaler

The use of Budesonide nasal inhaler with alternate-day systemic prednisone could increase the likelihood of hypothalamic-pituitary-adrenal (HPA) suppression compared with a therapeutic dose of either one alone. Therefore, Budesonide nasal inhaler should be used with caution in patients already receiving alternate-day prednisone treatment for any disease. In addition, the concomitant use of Budesonide nasal inhaler with other inhaled glucocorticosteroids could increase the risk of signs or symptoms of hypercorticism and/or suppression of the HPA-axis.

Additional Information for Budesonide Inhalation Powder

Particular care is needed for patients who are transferred from systemically active corticosteroids to Budesonide inhalation powder because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of HPA function. Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although Budesonide inhalation powder may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies. During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a medical identification card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.

Transfer of patients from systemic corticosteroid therapy to Budesonide inhalation powder may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, and eczema (see DOSAGE AND ADMINISTRATION).

Budesonide inhalation powder is not a bronchodilator and is not indicated for rapid relief of bronchospasm or other acute episodes of asthma.

As with other inhaled asthma medications, bronchospasm, with an immediate increase in wheezing, may occur after dosing. If bronchospasm occurs following dosing with Budesonide inhalation powder, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with Budesonide inhalation powder should be discontinued and alternate therapy instituted.

Patients should be instructed to contact their physician immediately when episodes of asthma not responsive to their usual doses of bronchodilators occur during treatment with Budesonide inhalation powder. During such episodes, patients may require therapy with oral corticosteroids.

PRECAUTIONS :

General
Budesonide Nasal Inhaler and Nasal Spray

Intranasal corticosteroids may cause a reduction in growth velocity when administered to pediatric patients (see Pediatric Use).

Rarely, immediate hypersensitivity reactions or contact dermatitis may occur after the intranasal administration of Budesonide. Rare instances of wheezing, nasal septum perforation, and increased intraocular pressure have been reported following the intranasal application of corticosteroids, including Budesonide.

Like other glucocorticosteroids, Budesonide is absorbed into the circulation. Use of excessive doses of glucocorticosteroids may lead to signs or symptoms of hypercorticism, suppression of HPA function and/or suppression of growth in children or teenagers. In short term studies of the acute effect of inhaled Budesonide 256 mug/day on lower leg growth (knemometry), it like other inhaled and intramuscular corticoids which have been studied showed a decrease in the rate of lower leg growth. The clinical significance of this finding is not known. In two one-year studies in 92 children taking recommended doses of Budesonide nasal inhaler, height and skeletal stature were consistent with chronological age. Physicians should closely follow the growth of children taking corticoids, by any route, and weigh the benefits of corticoid therapy against the possibility of growth suppression if a child’s growth appears slowed.

Although systemic effects have been minimal with recommended doses of Budesonide nasal inhaler and spray, any such effect is dose dependent. Therefore, larger than recommended doses of Budesonide nasal inhaler should be avoided, and the minimal effective dose for the patient should be used (see DOSAGE AND ADMINISTRATION). When used at larger doses, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of Budesonide nasal inhaler or spray should be discontinued slowly, consistent with accepted procedures for discontinuing oral glucocorticosteroid therapy.

In clinical studies with Budesonide administered intranasally, the development of localized infections of the nose and pharynx with Candida albicans has occurred in some patients. When such an infection develops, it may require treatment with appropriate local or systemic antifungal therapy and discontinuation of treatment with Budesonide nasal inhaler or spray. Patients using Budesonide nasal inhaler or spray over several months or longer should be examined periodically for evidence of Candida infection or other signs of adverse effects on the nasal mucosa.

Budesonide nasal inhaler or spray should be used with caution, if at all, in patients with active or quiescent tuberculous infections, untreated fungal, bacterial, or systemic viral infections, or ocular herpes simplex.

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 a nasal corticosteroid until healing has occurred.

Hepatic dysfunction influences the pharmacokinetics of Budesonide, similar to the effect on other corticosteroids, with a reduced elimination rate and increased systemic availability (see CLINICAL PHARMACOLOGY, Special Populations).

Budesonide Inhalation Powder

During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement of respiratory function.

Budesonide inhalation powder will often permit control of asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since Budesonide is absorbed into the circulation and can be systemically active at higher doses, the full beneficial effects of Budesonide inhalation powder in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing Budesonide inhalation powder.

Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with these drugs should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear in a small number of patients, particularly at higher doses. If such changes occur, Budesonide inhalation powder should be reduced slowly, consistent with accepted procedures for management of asthma symptoms and for tapering of systemic steroids.

A reduction of growth velocity in children or teenagers may occur as a result of inadequate control of chronic diseases such as asthma or from use of corticosteroids for treatment. Physicians should closely follow the growth of all pediatric patients taking corticosteroids by any route and weigh the benefits of corticosteroid therapy and asthma control against the possibility of growth suppression (see Pediatric Use).

Although patients in clinical trials have received Budesonide inhalation powder on a continuous basis for periods of 1 to 2 years, the long-term local and systemic effects of Budesonide inhalation powder in human subjects are not completely known. In particular, the effects resulting from chronic use of Budesonide inhalation powder on developmental or immunological processes in the mouth, pharynx, trachea, and lung are unknown.

In clinical trials with Budesonide inhalation powder, localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing with Budesonide inhalation powder therapy, but at times therapy with Budesonide inhalation powder may need to be temporarily interrupted under close medical supervision.

Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract, untreated systemic fungal, bacterial, viral or parasitic infections; or ocular herpes simplex.

Rare instances of glaucoma, increased intraocular pressure, and cataracts have been reported following the inhaled administration of corticosteroids.

Information for the Patient

Patients being treated with Budesonide should receive the following information and instructions: Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chicken pox or measle, and, if exposed, to obtain medical advice. Patients should also be advised that if they are exposed, they should consult their physician without delay.

Budesonide Nasal Inhaler

Patients should use Budesonide nasal inhaler as prescribed. A decrease in symptoms may occur as soon as 24 hours after initiation of treatment and generally can be expected to occur within a few days of initiating therapy in allergic rhinitis. The patient should contact the physician if symptoms do not improve by 3 weeks, or if the condition worsens. Nasal irritation and/or burning after use of the spray occur only rarely with this product. The patient should contact the physician if they occur repeatedly.

For the proper use of this unit and to attain maximum improvement, the patient should read and follow the patient instructions carefully.

Budesonide Nasal Spray

Patients should use Budesonide nasal spray at regular intervals since its effectiveness depends on its regular use (see DOSAGE AND ADMINISTRATION).

An improvement in nasal symptoms may be seen within the first 24 hours after initiation of treatment. Maximum benefit is generally not achieved until 2 weeks after initiation of treatment. Initial assessment for response should be made during this time frame and periodically until the patient’s symptoms are stabilized.

The patient should take the medication as directed and should not exceed the prescribed dosage. The patient should contact the physician if symptoms do not improve after two weeks, or if the condition worsens. Patients who experience recurrent episodes of epistaxis (nosebleeds) or nasal septum discomfort while taking this medication should contact their physician. For proper use of this unit and to attain maximum improvement, the patient should read and follow the accompanying patient instructions carefully.

It is important to shake the bottle well before each use. The Budesonide 32 mug bottle should be discarded after 60 or 120 sprays after initial priming and the Budesonide 64 mug bottle should be discarded after 120 sprays, after initial priming, since the amount of Budesonide delivered per spray thereafter may be substantially less than the labeled dose. Do not transfer any remaining suspension to another bottle.

Budesonide Inhalation Powder

For proper use of Budesonide inhalation powder and to attain maximum improvement, the patient should read and follow the PATIENT PACKAGE INSERT carefully. In addition, patients being treated with Budesonide inhalation powder should receive the following information and instructions. This information is intended to aid the patient in the safe and effective use of the medication. It is not a disclosure of all possible adverse or intended effects.

  • Patients should use Budesonide inhalation powder at regular intervals as directed since its effectiveness depends on regular use. The patient should not alter the prescribed dosage unless advised to do so by the physician.
  • Budesonide inhalation powder is not a bronchodilator and is not intended to treat acute or life-threatening episodes of asthma.
  • Budesonide inhalation powder must be in the upright position (mouthpiece on top) during loading in order to provide the correct dose. Budesonide inhalation powder must be primed when the unit is used for the very first time. To prime the unit, hold the unit in an upright position and turn the brown grip fully to the right, then fully to the left until it clicks. Repeat. The unit is now primed and ready to load the first dose by turning the grip fully to the right and fully to the left until it clicks.
  • On subsequent uses, it is not necessary to prime the unit. However, it must be loaded in the upright position immediately prior to use. Turn the brown grip fully to the right, then fully to the left until it clicks. During inhalation, Budesonide inhalation powder must be held in the upright (mouthpiece up) or horizontal position. Do not shake the inhaler. Place the mouthpiece between lips and inhale forcefully and deeply. The powder is then delivered to the lungs.
  • Patients should not exhale through Budesonide inhalation powder.
  • Due to the small volume of powder, the patient may not taste or sense the presence of any medication entering the lungs when inhaling from the inhaler. This lack of “sensation” does not indicate that the patient is not receiving benefit from Budesonide inhalation powder.
  • Rinsing the mouth with water without swallowing after each dosing may decrease the risk of the development of oral candidiasis.
  • When there are 20 doses remaining in Budesonide inhalation powder, a red mark will appear in the indicator window.
  • Budesonide inhalation powder should not be used with a spacer.
  • The mouthpiece should not be bitten or chewed.
  • The cover should be replaced securely after each opening.
  • Keep Budesonide inhalation powder clean and dry at all times.
  • Improvement in asthma control following inhalation of Budesonide inhalation powder can occur within 24 hours of beginning treatment although maximum benefit may not be achieved for 1 to 2 weeks, or longer. If symptoms do not improve in that time frame, or if the condition worsens, the patient should be instructed to contact the physician.
  • Patients should be warned to avoid exposure to chicken pox or measles and if they are exposed, to consult their physicians without delay.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term studies were conducted in mice and rats using oral administration to evaluate the carcinogenic potential of Budesonide.

There was no evidence of a carcinogenic effect when Budesonide was administered orally for 91 weeks to mice at doses up to 200 mug/kg/day (600 mug/m2/day or approximately 3 times the maximum recommended daily dose in adults and children on a mug/m2 basis or ¼ the maximum recommended daily inhalation dose on a mug/m2 basis).

In a two-year study in Sprague-Dawley rats, Budesonide caused a statistically significant increase in the incidence of gliomas in the male rats receiving an oral dose of 50 mug/kg (approximately twice the maximum recommended daily intranasal dose in adults and children on a mug/m2 basis). No tumorigenicity was seen in male and female rats at respective oral doses up to 25 and 50 mug/kg (approximately equal to and 2 times the maximum recommended daily intranasal dose in adults and children on a mug/m2 basis or 1/8 and 1/4 the maximum recommended daily inhalation powder dose on a mug/m2 basis, respectively). In two additional two-year studies in male Fischer and Sprague-Dawley rats, Budesonide caused no gliomas at an oral dose of 50 mug/kg (approximately twice the maximum recommended daily intranasal dose in adults and children on a mug/m2 basis or ¼ the maximum recommended daily inhalation powder dose). However, in male Sprague-Dawley rats, Budesonide caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mug/kg (approximately twice the maximum recommended daily intranasal dose in adults and children on a mug/m2 basis or 1/3 the maximum recommended daily inhalation powder dose on a mug/m2 basis). The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide) in these two studies showed similar findings.

Budesonide was not mutagenic or clastogenic in six different test systems: Ames Salmonella /microsome plate test, mouse micronucleus test, mouse lymphoma test, chromosome aberration test in human lymphocytes, sex-linked recessive lethal test in Drosophila melanogaster , and DNA repair analysis in rat hepatocyte culture.

The effect upon fertility and general reproductive performance was studied in rats given Budesonide subcutaneously. At 20 mug/kg/day (120 mug/m2/day) and higher dose levels, a decrease in maternal body-weight gain was observed along with a decrease in prenatal viability and viability of the young at birth and during lactation. No such effects were noted at the dose level 5 mug/kg/day (30 mug/m2/day).

In rats, Budesonide caused a decrease in prenatal viability and viability of the pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mug/kg and above (less than the maximum recommended daily intranasal dose in adults on a mug/m2 basis and approximately 1/8 the maximum recommended daily inhalation dose in adults on a mug/m2 basis). No such effects were noted at 5 mug/kg (less than the maximum recommended daily intranasal dose in adults on a mug/m2 basis and 1/32 the maximum recommended daily inhalation dose in adults on a mug/m2 basis).

Pregnancy, Teratogenic Effects, Pregnancy Category C

Teratogenic Effects: Pregnancy Category C: Budesonide was teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at subcutaneous doses of 25 mug/kg in rabbits and 500 mug/kg in rats (approximately 2 and 16 times the maximum recommended daily intranasal dose in adults on a mug/m2 basis, and 1/3 and 3 times the maximum recommended daily inhalation dose in adults on a mug/m2 basis, respectively). In another study in rats, no teratogenic or embryocidal effects were seen at inhalation doses up to 250 mug/kg (approximately 8 times the maximum recommended daily intranasal dose and 2 times the maximum recommended daily inhalation dose in adults on a mug/m2 basis).

There are no adequate and well-controlled studies in pregnant women. Budesonide 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. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy.

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 Budesonide is excreted in human milk. Because other corticosteroids are excreted in human milk, caution should be exercised when Budesonide is administered to nursing women.

Pediatric Use

Safety and effectiveness in pediatric patients below 6 years of age have not been established.

Additional Information for Budesonide Nasal Spray And Nasal Inhaler : Controlled clinical studies 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 this 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 Budesonide, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of safe and effective noncorticosteroid treatment alternatives. To minimize the systemic effects of intranasal corticosteroids, including Budesonide, each patient should be titrated to the lowest dose that effectively controls his/her symptoms.

Additional Information for Budesonide Inhalation Powder : In pediatric asthma patients the frequency of adverse events observed with Budesonide inhalation powder was similar between the 6- to 12-year age group (N=172) compared with the 13- to 17-year age group (N=124).

Oral corticosteroids have been shown to cause growth suppression in pediatric and adolescent patients, particularly with higher doses over extended periods. If a pediatric or adolescent patient on any corticosteroid appears to have growth suppression, the possibility that they are particularly sensitive to this effect of corticosteroids should be considered.

Geriatric Use

Budesonide Nasal Spray : Of the 2461 patients in clinical studies of Budesonide nasal spray, 5% were 60 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, except for an adverse event reporting frequency of epistaxis which increased with age. Further, other reported clinical experience has not identified any other differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Budesonide Inhalation Powder : One hundred patients 65 years or older were included in the US and non-US controlled clinical trials of Budesonide inhalation powder. There were no differences in the safety and efficacy of the drug compared to those seen in younger patients.

DRUG INTERACTIONS :

The main route of metabolism of Budesonide, as well as other corticosteroids, is via cytochrome P450 3A (CYP3A). After oral administration of ketoconazole, a potent inhibitor of cytochrome P450 3A, the mean plasma concentration of orally administered Budesonide increased by more than sevenfold. Concomitant administration of other known inhibitors of CYP3A (e.g., itraconazole, clarithromycin, erythromycin, etc.) may inhibit the metabolism of, and increase the systemic exposure to, Budesonide (see WARNINGS and PRECAUTIONS, General).

Omeprazole, an inhibitor of cytochrome P450 2C19, did not have effects on the pharmacokinetics of oral Budesonide, while cimetidine, primarily an inhibitor of cytochrome P450 1A2, caused a slight decrease in Budesonide clearance and corresponding increase in its oral bioavailability.

Additional Information for Budesonide Inhalation Powder : In clinical studies, concurrent administration of Budesonide and other drugs commonly used in the treatment of asthma has not resulted in an increased frequency of adverse events. Ketoconazole, a potent inhibitor of cytochrome P450 3A, may increase plasma levels of Budesonide during concomitant dosing. The clinical significance of concomitant administration of ketoconazole with Budesonide inhalation powder is not known, but caution may be warranted.

ADVERSE REACTIONS :

If recommended doses are exceeded, or if individuals are particularly sensitive, symptoms of hypercorticism (i.e., Cushing’s syndrome) could occur.

Budesonide Nasal Inhaler

Adverse reaction information is derived from blinded-controlled clinical trials (see CLINICAL STUDIES), open label studies and marketing experience. In the description below, rates of rare events are derived principally from marketing experience and publications, and accurate estimates of incidence are not possible.

The incidence of common adverse reactions is based upon controlled clinical trials in 606 patients [101 girls and 145 boys (<19 years of age) and 203 female and 157 male adults] treated with Budesonide nasal inhaler 128 mug twice daily over 2-4 weeks. The most common adverse reactions were symptoms of irritation of the nasal mucous membranes. All common adverse reactions were reported with approximately the same frequency by placebo patients suggesting the possibility that the vehicle of the rhinitis itself was responsible for the symptoms. Sneezing after use of the inhaler occurred in 2% of Budesonide treated patients and in 11% of patients using the placebo.

Systemic corticosteroid side-effects were not reported during controlled clinical studies with Budesonide nasal inhaler.

Incidence Greater than 1%: (Based on controlled clinical trials).

Respiratory: Nasal irritation*, pharyngitis*, cough increased*, epistaxis*.
Digestive: Dry mouth, dyspepsia.

* Incidence 3-9%; incidence of unmarked reactions 1-3%.

Incidence Less than 1%: (Based on controlled clinical trials).

Respiratory : Dyspnea, moniliasis, hoarseness, wheezing, nasal pain.
Special Senses : Reduced sense of smell, bad taste.
Digestive : Nausea.
Skin and Appendages : Facial edema, rash, pruritus, herpes simplex.
Nervous System : Nervousness.
Musculoskeletal : Myalgia, arthralgia

Adverse Event Reports from Other Sources Rare Adverse Events Reported in the Published Literature or from Marketing Experience Include: Immediate and delayed hypersensitivity reactions including rash, contact dermatitis, utricaria, angioedema, and bronchospasm; nasal septal disorders including atrophy, necrosis and/or perforation; symptoms of hypocorticism and hypercorticism; alopecia; psychiatric symptoms including depression, aggressive reactions, irritability, anxiety, and psychosis.

Budesonide Nasal Spray

The incidence of common adverse reactions is based upon two U.S. and five non-U.S. controlled clinical trials in 1526 patients [110 females and 239 males less than 18 years of age, and 635 females and 542 males 18 years of age and older] treated with Budesonide at doses up to 400 mug once daily for 3-6 weeks. TABLE 2 describes adverse events occurring at an incidence of 2% or greater and more common among Budesonide-treated patients than in placebo-treated patients in controlled clinical trials. The overall incidence of adverse events was similar between Budesonide nasal spray and placebo.

TABLE 2
Adverse Event
Budesonide Nasal Spray
Placebo Vehicle
Epistaxis
8%
5%
Pharyngitis
4%
3%
Bronchospasm
2%
1%
Coughing
2%
<1%
Nasal Irritation
2%
<1%

A similar adverse event profile was observed in the subgroup of pediatric patients 6-12 years of age.

Two to three percent (2-3%) of patients in clinical trials discontinued because of adverse events. Systemic corticosteroid side-effects were not reported during controlled clinical studies with Budesonide.

If recommended doses are exceeded, however, or if individuals are particularly sensitive, symptoms of hypercorticism (i.e., Cushing’s Syndrome) could occur.

Rare adverse events reported from post-marketing experience include: nasal septum perforation, pharynx disorders (throat irritation, throat pain, swollen throat, burning throat, and itchy throat), angioedema, anosmia, and palpitations.

Cases of growth suppression have been reported for intranasal corticosteroids including Budesonide (see PRECAUTIONS, Pediatric Use).

Budesonide Inhalation Powder

The following adverse reactions were reported in patients treated with Budesonide inhalation powder.

The incidence of common adverse events is based upon double-blind, placebo-controlled US clinical trials in which 1116 adult and pediatric patients age 6-70 years (472 females and 644 males) were treated with Budesonide inhalation powder (200-800 mug twice daily for 12-20 weeks) or placebo.

TABLE 3 shows the incidence of adverse events in patients previously receiving bronchodilators and/or inhaled corticosteroids in US controlled clinical trials. This population included 232 male and 62 female pediatric patients (age 6-17 years) and 332 male and 331 female adult patients (age 18 years and greater).

TABLE 3 Adverse Events with >3% Incidence Reported by Patients on Budesonide Inhalation Powder
Adverse Event
Placebo N=284 %
Budesonide Inhalation Powder
200 mug twice daily N=286 %
400 mug twice daily N=289 %
800 mug twice daily N=98 %
Respiratory System
Respiratory infection
17
20
24
19
Pharyngitis
9
10
9
5
Sinusitis
7
11
7
2
Voice alteration
0
1
2
6
Body as a Whole
Headache
7
14
13
14
Flu syndrome
6
6
6
14
Pain
2
5
5
5
Back pain
1
2
3
6
Fever
2
2
4
0
Digestive System
Oral candidiasis
2
2
4
4
Dyspepsia
2
1
2
4
Gastroenteritis
1
1
2
3
Nausea
2
2
1
3
Average Duration of Exposure (days)
59
79
80
80

TABLE 3 includes all events (whether considered drug-related or non drug-related by the investigators) that occurred at a rate of 3% in any one Budesonide inhalation powder group and were more common than in the placebo group. In considering these data, the increased average duration of exposure for Budesonide inhalation powder patients should be taken into account.

The Following Other Adverse Events Occurred in These Clinical Trials Using Budesonide Inhalation Powder with an Incidence of 1-3% and Were More Common on Pulmicort Turbuhaler than on Placebo:

Body as a Whole : Neck pain.
Cardiovascular : Syncope.
Digestive : Abdominal pain, dry mouth, vomiting.
Metabolic and Nutritional : Weight gain.
Musculoskeletal : Fracture, myalgia.
Nervous : Hypertonia, migraine.
Platelet, Bleeding, and Clotting : Ecchymosis.
Psychiatric : Insomnia.
Resistance Mechanisms : Infection.
Special Senses : Taste perversion.

In a 20-week trial in adult asthmatics who previously required oral corticosteroids, the effects of Budesonide inhalation powder 400 mug twice daily (N=53) and 800 mug twice daily (N=53) were compared with placebo (N=53) on the frequency of reported adverse events. Adverse events, whether considered drug-related or non drug-related by the investigators, reported in more than 5 patients in the Budesonide inhalation powder group and which occurred more frequently with Budesonide inhalation powder than placebo are shown below (% Budesonide inhalation powder and % placebo). In considering these data, the increased average duration of exposure for Budesonide inhalation powder patients (78 days for Budesonide inhalation powder vs. 41 days for placebo) should be taken into account.

Body as a Whole : Asthenia (9% and 2%); headache (12% and 2%); pain (10% and 2%).
Digestive : Dyspepsia (8% and 0%); nausea (6% and 0%); oral candidiasis (10% and 0%).
Musculoskeletal : Arthralgia (6% and 0%).
Respiratory : Cough increased (6% and 2%); respiratory infection (32% and 13%); rhinitis (6% and 2%); sinusitis (16% and 11%).

Patient Receiving Budesonide Inhalation Powder Once Daily : The adverse event profile of once-daily administration of Budesonide inhalation powder 200 mug and 400 mug, and placebo, was evaluated in 309 adult asthmatic patients in an 18-week study. The study population included both patients previously treated with inhaled corticosteroids, and patients not previously receiving corticosteroid therapy. There was no clinically relevant difference in the pattern of adverse events following once-daily administration of Budesonide inhalation powder when compared to twice-daily dosing.

Pediatric Studies : In a 12-week placebo-controlled trial in 404 pediatric patients 6-18 years of age previously maintained on inhaled corticosteroids, the frequency of adverse events for each age category (6-12 years, 13-18 years) was comparable for Budesonide inhalation powder (at 100, 200, and 400 mug twice daily) and placebo. There were no clinically relevant differences in the pattern or severity of adverse events in children compared with those reported in adults.

Adverse Event Reports From Other Sources : Rare adverse events reported in the published literature or from marketing experience include: immediate and delayed hypersensitivity reactions including rash, contact dermatitis, urticaria, angioedema and bronchospasm; symptoms of hypocorticism and hypercorticism; psychiatric symptoms including depression, aggressive reactions, irritability, anxiety, and psychosis.

OVERDOSAGE :

Budesonide Nasal Inhaler

Acute overdosage with this dosage form is unlikely since one canister of Budesonide nasal inhaler only contains approximately 12.7 mg of Budesonide. Chronic overdosage may result in signs/symptoms of hypercorticism (see WARNINGS and PRECAUTIONS).

Budesonide Nasal Spray

Acute overdosage with this dosage form is unlikely since one 60 spray bottle of Budesonide nasal spray 32 mug only contains approximately 3.2 mg of Budesonide, one 120 spray bottle of Budesonide nasal spray 32 mug contains approximately 5.4 mg of Budesonide, and one 120 spray bottle of Budesonide nasal spray 64 mug only contains approximately 10.8 mg of Budesonide. Chronic overdosage may result in signs/symptoms of hypercorticism (see WARNINGS and PRECAUTIONS).

Budesonide Inhalation Powder

The potential for acute toxic effects following overdose of Budesonide inhalation powder is low. If used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism may occur (see PRECAUTIONS). Budesonide inhalation powder at twice the highest recommended dose (3200 mug daily) administered for 6 weeks caused a significant reduction (27%) in the plasma cortisol response to a 6-hour infusion of ACTH compared with placebo (+1%). The corresponding effect of 10 mg prednisone daily was a 35% reduction in the plasma cortisol response to ACTH.

The minimal inhalation lethal dose in mice was 100 mg/kg (approximately 320 times the maximum recommended daily inhalation dose in adults and approximately 380 times the maximum recommended daily inhalation dose in children on a mug/m2 basis). There were no deaths following the administration of an inhalation dose of 68 mg/kg in rats (approximately 430 times the maximum recommended daily inhalation dose in adults and approximately 510 times the maximum recommended daily inhalation dose in children on a mug/m2 basis). The minimal oral lethal dose was 200 mg/kg in mice (approximately 630 times the maximum recommended daily inhalation dose in adults and approximately 750 times the maximum recommended daily inhalation dose in children on a mug/m2 basis) and less than 100 mg/kg in rats (approximately 630 times the maximum recommended daily inhalation dose in adults and approximately 750 times the maximum recommended daily inhalation dose in children on a mug/m2 basis).

DOSAGE AND ADMINISTRATION :

Budesonide Nasal Inhaler

Adults and Children 6 Years of Age and Older Individualization Of Dosage: It is recommended that the starting dose for all adults be 256 mug daily, as either 2 sprays in each nostril twice per day, morning and evening, or as 4 sprays in each nostril once a day in the morning. The effect should be assessed 3-7 days after initiating treatment and then periodically until the patient’s symptoms are stable.

If adequate relief of symptoms is not achieved after 3 weeks of treatment, then Budesonide nasal inhaler should be discontinued.

In patients who do achieve a good result it is desirable, once the maximum benefit seems to have been achieved, to titrate an individual patient to the minimum effective dose.

Because of the generally short duration of therapy for seasonal allergic rhinitis, it is usually not necessary to do this.

In patients with perennial allergic rhinitis, once adequate relief has been obtained the dose should be gradually decreased every 2-4 weeks as long as the desired clinical effect is maintained. If symptoms return, the dose may briefly be increased to the patient’s starting dose and then returned to the dose the patient was on before symptoms reoccurred.

As with other aerosolized nasal corticosteroids, the vehicle used to deliver the corticosteroid may cause symptoms that are difficult to distinguish from the patient’s rhinitis symptoms. The corticoid may suppress symptoms caused by the vehicle at higher doses but as the dose is decreased symptoms from the vehicle may emerge. If a patient needs chronic treatment and the daily dose cannot be decreased from the starting dose, it may be advisable to try alternative therapy.

If corticosteroids are discontinued when they still are needed, symptoms may not recur for several days.

At recommended doses, Budesonide’s therapeutic effects are localized to the nose, therefore, concomitant treatment may be necessary to counteract allergic eye symptoms. Doses exceeding 256 mug daily (4 sprays/nostril) are not recommended. Budesonide nasal inhaler is not recommended for children below 6 years of age or for children with nonallergic perennial rhinitis because adequate numbers of these children have not been studied.

Budesonide Nasal Spray

The Recommended Starting Dose for Adults and Children 6 Years of Age and Older : 64 mug per day administered as 1 spray per nostril of Budesonide 32 mug nasal spray once daily. The maximum recommended dose for adults (12 years of age and older) is 256 mug per day administered as 4 sprays per nostril once daily of Budesonide 32 mug nasal spray, or as 2 sprays per nostril once daily of Budesonide 64 mug nasal spray, and the maximum recommended dose for pediatrics (<12 years of age) is 128 mug per day administered as 2 sprays per nostril once daily of Budesonide 32 mug nasal spray or 1 spray per nostril once daily of Budesonide (see HOW SUPPLIED).

Prior to initial use, the container must be shaken gently and the pump must be primed by actuating 8 times. If used daily, the pump does not need to be reprimed. If not used for 2 consecutive days, reprime with 1 spray or until a fine spray appears. If not used for more than 14 days, rinse the applicator and reprime with 2 sprays or until a fine spray appears.

Individualization of Dosage : It is always desirable to titrate an individual patient to the minimum effective dose to reduce the possibility of side effects. In adults and children 6 years of age and older, the recommended starting dose is 64 mug daily administered as 1 spray per nostril of Budesonide 32 mug, once-daily. Some patients who do not achieve symptom control at the recommended starting dose may benefit from an increased dose. The maximum daily dose is 256 mug for adults and 128 mug for pediatric patients (<12 years of age). When the maximum benefit has been achieved and symptoms have been controlled, reducing the dose may be effective in maintaining control of the allergic rhinitis symptoms in patients who were initially controlled on higher doses.

An improvement in symptoms may be seen in some patients within the first 24 hours after initiating treatment. Maximum benefit is generally not achieved until 2 weeks after initiation of treatment. Initial assessment for response should be made during this time frame and periodically until the patient’s symptoms are stabilized.

Budesonide Inhalation Powder

Budesonide inhalation powder should be administered by the orally inhaled route in asthmatic patients age 6 years and older. Individual patients will experience a variable onset and degree of symptom relief. Generally, Budesonide inhalation powder has a relatively rapid onset of action for an inhaled corticosteroid. Improvement in asthma control following inhaled administration of Budesonide inhalation powder can occur within 24 hours of initiation of treatment, although maximum benefit may not be achieved for 1-2 weeks, or longer. The safety and efficacy of Budesonide inhalation powder when administered in excess of recommended doses have not been established.

The recommended starting dose and the highest recommended dose of Budesonide inhalation powder, based on prior asthma therapy, are listed in TABLE 4.

TABLE 4
Previous Therapy
Recommended Starting Dose
Highest Recommended Dose
Adults
Bronchodilators alone
200-400 mug twice daily
400 mug twice daily
Inhaled Corticosteroids*
200-400 mug twice daily
800 mug twice daily
Oral Corticosteroids
400-800 mug twice daily
800 mug twice daily
Children
Bronchodilators alone
200 mug twice daily
400 mug twice daily
Inhaled Corticosteroids*
200 mug twice daily
400 mug twice daily
Oral Corticosteroids
The highest recommended dose in children is 400 mug twice daily
* In patients with mild to moderate asthma who are well controlled on inhaled corticosteroids, dosing with Budesonide inhalation powder 200 mug or 400 mug once daily may be considered. Budesonide inhalation powder can be administered once daily either in the morning or in the evening.

If the once-daily treatment with Budesonide inhalation powder does not provide adequate control of asthma symptoms, the total daily dose should be increased and/or administered as a divided dose.

Patients Maintained on Chronic Oral Corticosteroids : Initially, Budesonide inhalation powder should be used concurrently with the patient’s usual maintenance dose of systemic corticosteroid. After approximately one week, gradual withdrawal of the systemic corticosteroid is started by reducing the daily or alternate daily dose. The next reduction is made after an interval of 1 or 2 weeks, depending on the response of the patient. Generally, these decrements should not exceed 2.5 mg of prednisone or its equivalent. A slow rate of withdrawal is strongly recommended. During reduction of oral corticosteroids, patients should be carefully monitored for asthma instability, including objective measures of airway function, and for adrenal insufficiency (see WARNINGS). During withdrawal, some patients may experience symptoms of systemic corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude and depression, despite maintenance or even improvement in pulmonary function. Such patients should be encouraged to continue with Budesonide inhalation powder but should be monitored for objective signs of adrenal insufficiency. If evidence of adrenal insufficiency occurs, the systemic corticosteroid doses should be increased temporarily and thereafter withdrawal should continue more slowly. During periods of stress or a severe asthma attack, transfer patients may require supplementary treatment with systemic corticosteroids.

NOTE : In all patients it is desirable to titrate to the lowest effective dose once asthma stability is achieved.

Patients should be instructed to prime the Budesonide inhalation powder inhaler prior to its initial use, and instructed to inhale deeply and forcefully each time the unit is used. Rinsing the mouth after inhalation is also recommended.

PATIENT PACKAGE INSERT :

Rhinocort Nasal Inhaler : Use a pair of scissors to cut the pouch open. Read the information before using Budesonide nasal inhaler. Follow the directions carefully.

1. Blow your nose. Open the nasal adapter by pressing on the arrow and rotating until it clicks into the locked position. Shake the canister thoroughly before using.

2. Place your thumb on the bottom of the unit (on the grid) while placing your index finger on the top of the canister. Wrap your fingers securely around the back. Press straight down on the canister to deliver a dose. Spray into the air 4 times before using for the first time

3. Close one nostril and insert the extreme end of the tube into the other nostril. Hold your breath and actuate a dose by pressing on the canister. Administer the prescribed dose in the other nostril in the same way.

4. Close the nasal adapter by pressing under the tube on the light gray part. Revolve the light gray part until it comes into a locked position.

Warning : Contains trichloromonofluoromethane, dichlorotetra-fluoroethane, and dichlorodifluoromethane, substances which harm the environment by destroying ozone in the upper atmosphere. Your physician has determined that this product is likely to help your personal health. USE THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE BY YOUR PHYSICIAN. If you have any questions about alternatives, consult with your physician.

Follow your doctor’s directions and do not use Rhinocort Nasal Inhaler more often than prescribed. Contact your doctor if you find the effect strongly reduced. Rhinocort Nasal Inhaler does not give immediate relief. Generally it will take a few days to achieve full effect. It is therefore very important that Rhinocort is used regularly morning and evening.

Rhinocort Nasal Inhaler should be used within 6 months after the aluminum pouch has been opened. After opening the pouch, avoid storage in areas of high humidity.

Cleaning

Remove the aerosol container and wash the plastic parts regularly in warm–not hot–water with addition of mild detergent if necessary. Allow the plastic parts to dry completely and then replace the container.

Contents under pressure

Do not puncture or throw container into incinerator. Using or storing near open flame or heating above 120°F (50°C) may cause container to burst.


HOW SUPPLIED :

Budesonide Nasal Inhaler

Each actuation delivers approximately 32 mug of micronized Budesonide from the nasal adapter to the patient.

Storage : Rhinocort Nasal Inhaler should be stored between 15-30°C (59-86°F) with the valve up. Shake well before use. After opening the aluminum pouch, the product should be used within 6 months and storage in an area of high humidity should be avoided.

Contents Under Pressure : Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 50°C (120°F) may cause the canister to explode. Never throw the container into fire or an incinerator. Keep out of reach of children.

NOTE : The statement below is required by the Federal government’s Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFCs).

WARNING : Contains trichloromonofluoromethane, dichlorotetrafluoroethane, and dichlorodifluoromethane, substances which harm public health and environment by destroying ozone in the upper atmosphere.

Budesonide Nasal Spray

Rhinocort aqua nasal spray is available in two strengths (32 mug and 64 mug).

Storage : Rhinocort Aqua nasal spray should be stored at controlled room temperature, 20-25°C (68-77°F) with the valve up. Do not freeze. Protect from light. Shake gently before use. Do not spray in eyes.

Budesonide Inhalation Powder

Turbuhaler cannot be refilled and should be discarded when empty.

Storage : Store at controlled room temperature 20-25°C (68-77°F).

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