Budesonide (3201)

CATEGORIES, DRUG CLASSES, BRAND NAMES & COST OF THERAPY

Note: The trade names have been used throughout this monograph for clarity.

Pulmicort Respules

For inhalation use via compressed air driven jet nebulizers only (not for use with ultrasonic devices). Not for injection. Read patient instructions before using.

Budesonide, the active component of Pulmicort Respules, is a corticosteroid designated chemically as (RS)-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide is provided as a 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. Its partition coefficient between octanol and water at pH 7.4 is 1.6 × 10³.

Pulmicort Respules is a sterile suspension for inhalation via jet nebulizer and contains the active ingredient budesonide (micronized), and the inactive ingredients disodium edetate, sodium chloride, sodium citrate, citric acid, polysorbate 80 and water for injection. Two dose strengths are available in single-dose ampules (Respules ampules): 0.25 and 0.5 mg/2 ml Respule ampule. For Pulmicort Respules, like all other nebulized treatments, the amount delivered to the lungs will depend on patient factors, the jet nebulizer utilized, and compressor performance. Using the Pari-LC-Jet Plus Nebulizer/PariMaster compressor system, under in vitro conditions, the mean delivered dose at the mouthpiece (% nominal dose) was approximately 17% at a mean flow rate of 5.5 L/min. The mean nebulization time was 5 minutes or less. Pulmicort Respules should be administered from jet nebulizers at adequate flow rates, via face masks or mouthpieces (see DOSAGE AND ADMINISTRATION, Pulmicort Respules).

Pulmicort Turbuhaler

For Oral Inhalation Only.

Budesonide, the active component of Pulmicort Turbuhaler 200 μg, is a corticosteroid designated chemically as (RS)-11β,16α,17,21-Tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide is provided as a 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. Its partition coefficient between octanol and water at pH 7.4 is 1.6 × 10³.

Pulmicort Turbuhaler is an inhalation-driven multi-dose dry powder inhaler which contains only micronized budesonide. Each actuation of Pulmicort Turbuhaler provides 200 μg budesonide per metered dose, which delivers approximately 160 μg budesonide from the mouthpiece (based on in vitro testing at 60 L/min for 2 sec).

In vitro testing has shown that the dose delivery for Pulmicort Turbuhaler is substantially dependent on airflow through the device. Patient factors such as inspiratory flow rates will also affect the dose delivered to the lungs of patients in actual use (see Patient's Instructions for Use that accompany the prescription). 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 (6-15years, mean FEV₁ 2.1 L [0.9-5.4 L]). Patients should be carefully instructed on the use of this drug product to assure optimal dose delivery.

Pulmicort Respules

Mechanism of Action

Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro and animal models, budesonide has approximately a 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.

The precise mechanism of corticosteroid actions on inflammation in asthma is not well 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 non-allergic-mediated inflammation. The anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.

Studies in asthmatic patients have shown a favorable ratio between topical anti-inflammatory activities and systemic corticosteroid effects over a wide dose range of inhaled budesonide in a variety of formulations and delivery systems including Pulmicort Turbuhaler (an inhalation-driven, multi-dose dry powder inhaler) and the inhalation suspension for nebulization. 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 metabolites (see below).

Pharmacokinetics

The activity of Pulmicort Respules is due to the parent drug, budesonide. In glucocorticoid receptor affinity studies, the 22R form was 2 times as active as the 22S epimer. In vitro studies indicated that the two forms of budesonide do not interconvert.

Budesonide is primarily cleared by the liver. In asthmatic children 4-6 years of age, the terminal half-life of budesonide after nebulization is 2.3 hours, and the systemic clearance is 0.5 L/min, which is approximately 50% greater than in healthy adults after adjustment for differences in weight.

After a single dose of 1 mg budesonide, a peak plasma concentration of 2.6 nmol/L was obtained approximately 20 minutes after nebulization in asthmatic children 4-6 years of age. The exposure (AUC) of budesonide following administration of a single 1 mg dose of budesonide by nebulization to asthmatic children 4-6 years of age is comparable to healthy adults given a single 2 mg dose by nebulization.

Absorption

In asthmatic children 4-6 years of age, the total absolute bioavailability (i.e., lung + oral) following administration of Pulmicort Respules via jet nebulizer was approximately 6% of the labeled dose.

The peak plasma concentration of budesonide occurred 10-30 minutes after start of nebulization.

Distribution

In asthmatic children 4-6 years of age, the volume of distribution at steady-state of budesonide was 3 L/kg, approximately the same as in healthy adults. Budesonide is 85-90% bound to plasma proteins, the degree of binding being constant over the concentration range (1-100 nmol/L) achieved with, and exceeding, recommended doses. Budesonide showed little or no binding to corticosteroid-binding globulin. Budesonide rapidly equilibrated with red blood cells in a concentration independent manner with a blood/plasma ratio of about 0.8.

Metabolism

In vitro studies with human liver homogenates have shown that budesonide is rapidly and extensively metabolized. Two major metabolites formed via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4) catalyzed biotransformation have been isolated and identified as 16α-hydroxyprednisolone and 6β-hydroxybudesonide. The corticosteroid activity of each of these two metabolites is less than 1% of that of the parent compound. No qualitative difference between the in vitro and in vivo metabolic patterns has been detected. Negligible metabolic inactivation was observed in human lung and serum preparations.

Excretion

Budesonide is excreted in urine and feces in the form of metabolites. In adults, approximately 60% of an IV radiolabeled dose was recovered in the urine. No unchanged budesonide was detected in the urine.

Special Populations

No differences in pharmacokinetics due to race, gender, or age have been identified.

Hepatic Insufficiency

Reduced liver function may affect the elimination of corticosteroids. The pharmacokinetics of budesonide were affected by compromised liver function as evidenced by a doubled systemic availability after oral ingestion. The IV pharmacokinetics of budesonide were, however, similar in cirrhotic patients and in healthy adults.

Pharmacodynamics

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

Improvement in the control of asthma symptoms following inhalation of Pulmicort Respules can occur within 2-8 days of beginning treatment, although maximum benefit may not be achieved for 4-6 weeks.

Budesonide administered via Turbuhaler has been shown in various challenge models (including histamine, methacholine, sodium metabisulfite, and adenosine monophosphate) to decrease bronchial hyperresponsiveness in asthmatic patients. The clinical relevance of these models is not certain.

Pre-treatment with budesonide administered via Turbuhaler 1600 μg daily (800 μg 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 Pulmicort Respules on the hypothalamic-pituitary-adrenal (HPA) axis were studied in three, 12 week, double-blind, placebo-controlled studies in 293 pediatric patients, 6 months to 8 years of age, with persistent asthma. For most patients, the ability to increase cortisol production in response to stress, as assessed by the short cosyntropin (ACTH) stimulation test, remained intact with Pulmicort Respules treatment at recommended doses. In the subgroup of children age 6 months to 2 years (n=21) receiving a total daily dose of Pulmicort Respules equivalent to 0.25 mg (n=5), 0.5 mg (n=5), 1 mg (n=8), or placebo (n=3), the mean change from baseline in ACTH-stimulated cortisol levels showed a decline in peak stimulated cortisol at 12 weeks compared to an increase in the placebo group. These mean differences were not statistically significant compared to placebo. Another 12 week study in 141 pediatric patients 6-12 months of age with mild to moderate asthma or recurrent/persistent wheezing was conducted. All patients were randomized to receive either 0.5 or 1 mg of Pulmicort Respules or placebo once daily. A total of 28, 17, and 31 patients in the Pulmicort Respules 0.5 mg, 1 mg, and placebo arms respectively, had an evaluation of serum cortisol levels post-ACTH stimulation both at baseline and at the end of the study. The mean change from baseline to Week 12 ACTH-stimulated minus basal plasma cortisol levels did not indicate adrenal suppression in patients treated with Pulmicort Respules versus placebo. However, 7 patients in this study (4 of whom received Pulmicort Respules 0.5 mg, 2 of whom received Pulmicort Respules 1 mg and 1 of whom received placebo) showed a shift from normal baseline stimulated cortisol level (≥500 nmol/L) to a subnormal level (<500 nmol/L) at Week 12. In 4 of these patients receiving Pulmicort Respules, the cortisol values were near the cutoff value of 500 nmol/L.

The effects of Pulmicort Respules at doses of 0.5 mg twice daily, and 1 mg and 2 mg twice daily (2 times and 4 times the highest recommended total daily dose, respectively) on 24 hour urinary cortisol excretion were studied in 18 patients between 6-15 years of age with persistent asthma in a cross-over study design (4 weeks of treatment per dose level). There was a dose-related decrease in urinary cortisol excretion at 2 and 4 times the recommended daily dose. The two higher doses of Pulmicort Respules (1 and 2 mg twice daily) showed statistically significantly reduced (43-52%) urinary cortisol excretion compared to the run-in period. The highest recommended dose of Pulmicort Respules, 1 mg total daily dose, did not show statistically significantly reduced urinary cortisol excretion compared to the run-in period.

Pulmicort Respules, like other inhaled corticosteroid products, may impact the HPA axis, especially in susceptible individuals, in younger children, and in patients given high doses for prolonged periods.

Pulmicort Turbuhaler

Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro and animal models, budesonide has approximately a 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.

The precise mechanism of corticosteroid actions on inflammation in asthma 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 non-allergic-mediated inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.

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 Pulmicort Turbuhaler. 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 below).

Pharmacokinetics

The activity of Pulmicort Turbuhaler is due to the parent drug, budesonide. In glucocorticoid receptor affinity studies, the 22R form was 2 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. In asthmatic patients, budesonide showed a linear increase in AUC and C_max with increasing dose after both a single dose and repeated dosing from Pulmicort Turbuhaler.

Absorption

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 Pulmicort Turbuhaler.

Distribution

The volume of distribution of budesonide was approximately 3 L/kg. It was 85-90% bound to plasma proteins. Protein binding was constant over the concentration range (1-100 nmol/L) achieved with, and exceeding, recommended doses of Pulmicort Turbuhaler. Budesonide showed little or no binding to corticosteroid binding globulin. Budesonide rapidly equilibrated with red blood cells in a concentration independent manner with a blood/plasma ratio of about 0.8.

Metabolism

In vitro studies with human liver homogenates have shown that budesonide is rapidly and extensively metabolized. Two major metabolites formed via cytochrome P450 3A catalyzed biotransformation have been isolated and identified as 16α-hydroxyprednisolone and 6β-hydroxybudesonide. The corticosteroid activity of each of these two metabolites is less than 1% of that of the parent compound. No qualitative difference between the in vitro and in vivo metabolic patterns have been detected. Negligible metabolic inactivation was observed in human lung and serum preparations.

Excretion

Budesonide was excreted in urine and feces in the form of metabolites. Approximately 60% of an IV radiolabelled dose was recovered in the urine. No unchanged budesonide was detected in the urine.

Special Populations

No pharmacokinetic differences have been identified due to race, gender or advanced age.

Pediatric

Following IV dosing in pediatric patients age 10-14 years, plasma half-life was shorter than in adults (1.5 h vs 2.0 h 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.

Hepatic Insufficiency

Reduced liver function may affect the elimination of corticosteroids. The pharmacokinetics of budesonide were affected by compromised liver function as evidenced by a doubled systemic availability after oral ingestion. The IV pharmacokinetics of budesonide were, however, similar in cirrhotic patients and in healthy subjects.

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 effect on the pharmacokinetics of oral budesonide.

Pharmacodynamics

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 μg budesonide administered via a pressurized metered dose inhaler with a tube spacer to 1400 μg 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, Pulmicort Turbuhaler has a relatively rapid onset of action for an inhaled corticosteroid. Improvement in asthma control following inhalation of Pulmicort Turbuhaler can occur within 24 hours of beginning treatment although maximum benefit may not be achieved for 1-2 weeks, or longer.

Pulmicort Turbuhaler 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 Pulmicort Turbuhaler 1600 μg daily (800 μg 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 Pulmicort Turbuhaler 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 Pulmicort Turbuhaler treatment at recommended doses. For adult patients treated with 100, 200, 400, or 800 μg twice daily for 12 weeks, 4%, 2%, 6%, and 13% respectively, had an abnormal stimulated cortisol response (peak cortisol <14.5 μg/dl assessed by liquid chromatography following short-cosyntropintest) 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 μg budesonide twice daily via Pulmicort Turbuhaler for 6 weeks were examined; 1600 μg 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 Pulmicort Turbuhaler at doses of 400 and 800 μg twice daily met the criterion for an abnormal stimulated cortisol response (peak cortisol <14.5 μg/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 Pulmicort Turbuhaler when administered at recommended doses. In patients who had previously been oral steroid-dependent, use of Pulmicort Turbuhaler in recommended doses was associated with higher stimulated cortisol response compared to baseline following 1 year of therapy.

The administration of budesonide via Pulmicort Turbuhaler in doses up to 800 μg/day (mean daily dose 445 μg/day) or via a pressurized metered-dose inhaler in doses up to 1200 μg/day (mean daily dose 620 μg/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 Pulmicort Turbuhaler on growth is not fully known.

Pulmicort Respules

Three double-blind, placebo-controlled, parallel group, randomized US clinical trials of 12 weeks duration each were conducted in 1018 pediatric patients, 6 months to 8 years of age, with persistent asthma of varying disease duration (2-107 months) and severity. Doses of 0.25, 0.5, and 1 mg administered either once or twice daily were compared to placebo to provide information about appropriate dosing to cover a range of asthma severity. A Pari-LC-Jet Plus Nebulizer (with a face mask or mouthpiece) connected to a Pari Master compressor was used to deliver Pulmicort Respules to patients in the 3 US controlled clinical trials. The co-primary endpoints were nighttime and daytime asthma symptom scores (0-3 scale). Each of the 5 doses discussed below were studied in one or two, but not all three of the US studies.

Results of the 3 controlled clinical trials for recommended dosages of budesonide inhalation suspension (0.25-0.5 mg once or twice daily, or 1 mg once daily, up to a total daily dose of 1 mg) in 946 patients, 12 months to 8 years of age, are presented below. Compared to placebo, Pulmicort Respules significantly decreased both nighttime and daytime symptom scores of asthma at doses of 0.25 mg once daily (one study), 0.25 mg twice daily, and 0.5 mg twice daily. Pulmicort Respules significantly decreased either nighttime or daytime symptom scores, but not both, at doses of 1 mg once daily, and 0.5 mg once daily (one study). Symptom reduction in response to Pulmicort Respules occurred across gender and age. Pulmicort Respules significantly reduced the need for bronchodilator therapy at all the doses studied.

Improvements in lung function were associated with Pulmicort Respules in the subgroup of patients capable of performing lung function testing. Significant improvements were seen in FEV₁ [Pulmicort Respules 0.5 mg once daily and 1 mg once daily (one study); 0.5 mg twice daily] and morning PEF [Pulmicort Respules 1 mg once daily (one study); 0.25 mg twice daily; 0.5 mg twice daily] compared to placebo.

A numerical reduction in nighttime and daytime symptom scores (0-3 scale) of asthma was observed within 2-8 days, although maximum benefit was not achieved for 4-6 weeks after starting treatment. The reduction in nighttime and daytime asthma symptom scores was maintained throughout the 12 weeks of the double-blind trials.

Patients Not Receiving Inhaled Corticosteroid Therapy

The efficacy of Pulmicort Respules at doses of 0.25, 0.5, and 1 mg once daily was evaluated in 344 pediatric patients, 12 months to 8 years of age, with mild to moderate persistent asthma (mean baseline nighttime asthma symptom scores of the treatment groups ranged from 1.07-1.34) who were not well controlled by bronchodilators alone. Nighttime asthma symptom scores improved significantly in the patients treated with Pulmicort Respules compared to placebo. Similar improvements were also observed for daytime asthma symptom scores.

Patients Previously Maintained on Inhaled Corticosteroids

The efficacy of Pulmicort Respules at doses of 0.25 and 0.5 mg twice daily was evaluated in 133 pediatric asthma patients, 4-8 years of age, previously maintained on inhaled corticosteroids (mean FEV₁ 79.5% predicted; mean baseline nighttime asthma symptom scores of the treatment groups ranged from 1.04-1.18; mean baseline dose of beclomethasone dipropionate of 265 μg/day, ranging between 42-1008 μg/day; mean baseline dose of triamcinolone acetonide of 572 μg/day, ranging between 200-1200 μg/day). Nighttime asthma symptom scores were significantly improved in patients treated with Pulmicort Respules compared to placebo. Similar improvements were also observed for daytime asthma symptom scores.

Pulmicort Respules at a dose of 0.5 mg twice daily significantly improved FEV₁, and both doses (0.25 and 0.5 mg twice daily) significantly increased morning PEF, compared to placebo.

Patients Receiving Once-Daily or Twice-Daily Dosing

The efficacy of Pulmicort Respules at doses of 0.25 mg once daily, 0.25 mg twice daily, 0.5 mg twice daily, and 1 mg once daily, was evaluated in 469 pediatric patients 12 months to 8 years of age (mean baseline nighttime asthma symptom scores of the treatment groups ranged from 1.13-1.31). Approximately 70% were not previously receiving inhaled corticosteroids. Pulmicort Respules at doses of 0.25 and 0.5 mg twice daily, and 1 mg once daily, significantly improved nighttime asthma symptom scores compared to placebo. Similar improvements were also observed for daytime asthma symptom scores.

Pulmicort Respules at a dose of 0.5 mg twice daily significantly improved FEV₁, and at doses of 0.25 and 0.5 mg twice daily and 1 mg once daily significantly improved morning PEF, compared to placebo.

The evidence supports the efficacy of the same nominal dose of Pulmicort Respules administered on either a once-daily or twice-daily schedule. However, when all measures are considered together, the evidence is stronger for twice-daily dosing (see DOSAGE AND ADMINISTRATION, Pulmicort Respules).

Pulmicort Turbuhaler

The therapeutic efficacy of Pulmicort Turbuhaler 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, Pulmicort Turbuhaler 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 β₂-agonist use at doses of 400-1600 μg/day (200-800 μg twice daily) in adults and 400-800 μg/day (200-400 μg 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, Pulmicort Turbuhaler was evaluated at doses of 200 and 400 μg twice daily versus placebo. Pulmonary function improved significantly on both doses of Pulmicort Turbuhaler compared with placebo.

In a 12 month controlled trial in 75 patients not previously receiving corticosteroids, Pulmicort Turbuhaler at 200 μg 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 Pulmicort Turbuhaler 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 μg/day; pediatrics:n=404, mean baseline FEV₁ 2.09 L, baseline doses of beclomethasone dipropionate 126-672 μg/day or triamcinolone acetonide 300-1800 μg/day). Pulmonary function improved significantly with all doses of Pulmicort Turbuhaler compared to placebo in both trials.

Patients Receiving Pulmicort Turbuhaler Once Daily

The efficacy and safety of once-daily administration of Pulmicort Turbuhaler 200 and 400 μg 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 Pulmicort 200 or 400 μg 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 μg 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, Pulmicort Turbuhaler).

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) Pulmicort Turbuhaler at doses of 400 and 800 μg twice daily was compared to placebo over a 20 week period. Approximately two-thirds (68% on 400 μg twice daily and 64% on 800 μg twice daily) of Pulmicort Turbuhaler-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 μg twice daily and 79% on 800 μg twice daily for Pulmicort Turbuhaler-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 Pulmicort Turbuhaler.

Pulmicort Respules

Particular care is needed for patients who are transferred from systemically active corticosteroids to inhaled corticosteroids 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-axis 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-axis suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although Pulmicort Respules may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of corticosteroid 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 instructions. These patients should also be instructed to carry a warning 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 Pulmicort Respules may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, and eczema (see DOSAGE AND ADMINISTRATION, Pulmicort Respules).

Patients who are on drugs which suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible pediatric patients or adults on immunosuppressant doses of corticosteroids. In pediatric or adult patients who have not had these diseases, or who have not been properly vaccinated, 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 IV immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents may be considered.

Pulmicort Respules is not a bronchodilator and is not indicated for the rapid relief of acute 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 acute bronchospasm occurs following dosing with Pulmicort Respules, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with Pulmicort Respules 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 Pulmicort Respules.

Pulmicort Turbuhaler

Particular care is needed for patients who are transferred from systemically active corticosteroids to Pulmicort Turbuhaler 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 Pulmicort Turbuhaler 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 Pulmicort Turbuhaler may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, and eczema (see DOSAGE AND ADMINISTRATION, Pulmicort Turbuhaler).

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

Pulmicort Turbuhaler 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 Pulmicort Turbuhaler, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with Pulmicort Turbuhaler 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 Pulmicort Turbuhaler. During such episodes, patients may require therapy with oral corticosteroids.

Pulmicort Respules

General

Inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients (see Pulmicort Respules, Pediatric Use).

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.

Because budesonide is absorbed into the circulation and may be systemically active, particularly at higher doses, suppression of HPA function may be associated when Pulmicort Respules is administered at doses exceeding those recommended (see DOSAGE AND ADMINISTRATION, Pulmicort Respules), or when the dose is not titrated to the lowest effective dose. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing Pulmicort Respules.

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 post-operatively 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, Pulmicort Respules should be reduced slowly, consistent with accepted procedures for management of asthma symptoms and for tapering of systemic corticosteroids.

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

In clinical trials with Pulmicort Respules, localized infections with Candida albicans occurred in the mouth and pharynx in some patients. The incidences of localized infections of Candida albicans were similar between the placebo and Pulmicort Respules treatment groups. If symptomatic oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing with Pulmicort Respules therapy, but at times therapy with Pulmicort Respules may need to be 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

For instructions on the proper use of Pulmicort Respules and to attain the maximum improvement in asthma symptoms, the patient or the parent/guardian of the patient should receive, read, and follow the accompanying patient information and instructions carefully. In addition, patients being treated with Pulmicort Respules 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 take Pulmicort Respules at regular intervals once or twice a day 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.

The effects of mixing Pulmicort Respules with other nebulizable medications have not been adequately assessed. Pulmicort Respules should be administered separately in the nebulizer.

Pulmicort Respules is not a bronchodilator, and its use is not intended to treat acute life-threatening episodes of asthma.

Pulmicort Respules should be administered with a jet nebulizer connected to a compressor with an adequate air flow, equipped with a mouthpiece or suitable face mask. The face mask should be properly adjusted to optimize delivery and to avoid exposing the eyes to the nebulized medication (see DOSAGE AND ADMINISTRATION, Pulmicort Respules).

Ultrasonic nebulizers are not suitable for the adequate administration of Pulmicort Respules and, therefore, are not recommended (see DOSAGE AND ADMINISTRATION, Pulmicort Respules).

Rinsing the mouth with water after each treatment may decrease the risk of development of local candidiasis. Corticosteroid effects on the skin can be avoided if the face is washed after the use of a face mask.

Improvement in asthma control following treatment with Pulmicort Respules can occur within 2-8 days of beginning treatment, although maximum benefit may not be achieved for 4-6 weeks after starting treatment. If the asthma symptoms do not improve in that time frame, or if the condition worsens, the patient or the patient's parent/guardian should be instructed to contact the physician.

Care should be taken to avoid exposure to chicken pox and measles. If exposure occurs, and the child has not had chicken pox or been properly vaccinated, a physician should be consulted without delay.

Pulmicort Respules should be stored upright at controlled room temperature 20-25°C (68-77°F) and protected from light. Pulmicort Respules should not be refrigerated or frozen.

When an aluminum foil envelope has been opened, the shelf life of the unused Respules ampules is 2 weeks when protected from light. The date the envelope was opened should be recorded on the back of the envelope in the space provided.

After opening the aluminum foil envelope, the unused Respules ampules should be returned to the envelope to protect them from light. Any individually opened Respules ampules must be used promptly.

For proper usage of Pulmicort Respules and to attain maximum improvement, the Patient's Instructions for Use that accompany the prescription should be read and followed.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

In a 2 year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 μg/kg (less than the maximum recommended daily inhalation dose in adults and children on a μg/m² basis). No tumorigenicity was seen in male and female rats at respective oral doses up to 25 and 50 μg/kg (less than the maximum recommended daily inhalation dose in adults and children on a μg/m² basis). In two additional 2 year studies in male Fischer and Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 μg/kg (less than the maximum recommended daily inhalation dose in adults and children on a μg/m² basis). However, in the male Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 μg/kg (less than the maximum recommended daily inhalation dose in adults and children on a μg/m² basis). The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide) in these two studies showed similar findings.

In a 91 week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 μg/kg (less than the maximum recommended daily inhalation dose in adults and children on a μg/m² basis).

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.

In rats, budesonide had no effect on fertility at SC doses up to 80 μg/kg (less than the maximum recommended daily inhalation dose in adults on a μg/m² basis). However, it caused a decrease in prenatal viability and viability in the pups at birth and during lactation, along with a decrease in maternal body-weight gain, at SC doses of 20 μg/kg and above (less than the maximum recommended daily inhalation dose in adults on a μg/m² basis). No such effects were noted at 5 μg/kg (less than the maximum recommended daily inhalation dose in adults on a μg/m² basis).

Pregnancy Category B

Teratogenic Effects

As with other corticosteroids, budesonide was teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at SC doses of 25 μg/kg in rabbits (less than the maximum recommended daily inhalation dose in adults on a μg/m² basis) and 500 μg/kg in rats (approximately 4 times the maximum recommended daily inhalation dose in adults on a μg/m² basis). In another study in rats, no teratogenic or embryocidal effects were seen at inhalation doses up to 250 μg/kg (approximately 2 times the maximum recommended daily inhalation dose in adults on a μg/m² basis).

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.

Studies of pregnant women, however, have not shown that inhaled budesonide increases the risk of abnormalities when administered during pregnancy. The results from a large population-based prospective cohort epidemiological study reviewing data from three Swedish registries covering approximately 99% of the pregnancies from 1995-1997 (i.e., Swedish Medical Birth Registry; Registry of Congenital Malformations; Child Cardiology Registry) indicate no increased risk for congenital malformations from the use of inhaled budesonide during early pregnancy. Congenital malformations were studied in 2014 infants born to mothers reporting the use of inhaled budesonide for asthma in early pregnancy (usually 10-12 weeks after the last menstrual period), the period when most major organ malformations occur. The rate of recorded congenital malformations was similar compared to the general population rate (3.8% vs 3.5%, respectively). In addition, after exposure to inhaled budesonide, the number of infants born with orofacial clefts was similar to the expected number in the normal population (4 children vs 3.3, respectively).

These same data were utilized in a second study bringing the total to 2534 infants whose mothers were exposed to inhaled budesonide. In this study, the rate of congenital malformations among infants whose mothers were exposed to inhaled budesonide during early pregnancy was not different from the rate for all newborn babies during the same period (3.6%).

Despite the animal findings, it would appear that the possibility of fetal harm is remote if the drug is used during pregnancy. Nevertheless, because the studies in humans cannot rule out the possibility of harm, Pulmicort Respules should be used during pregnancy only if clearly needed.

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 if budesonide is administered to nursing women.

Pediatric Use

Safety in children 6–12 months of age has been evaluated. Safety and effectiveness in children 12 months to 8 years of age have been established (see CLINICAL PHARMACOLOGY, Pulmicort Respules, Pharmacodynamics; CLINICAL STUDIES, Pulmicort Respules; and ADVERSE REACTIONS, Pulmicort Respules).

A 12 week study in 141 pediatric patients 6-12 months of age with mild to moderate asthma or recurrent/persistent wheezing was conducted. All patients were randomized to receive either 0.5 or 1 mg of Pulmicort Respules or placebo once daily. Adrenal axis function was assessed with an ACTH stimulation test at the beginning and end of the study, and mean changes from baseline in this variable did not indicate adrenal suppression in patients who received Pulmicort Respules versus placebo. However, on an individual basis, 7 patients in this study (6 in the Pulmicort Respules treatment arms and 1 in the placebo arm) experienced a shift from having a normal baseline stimulated cortisol level to having a subnormal level at Week 12 (see CLINICAL PHARMACOLOGY, Pulmicort Respules, Pharmacodynamics). Pneumonia was observed more frequently in patients treated with Pulmicort Respules than in patients treated with placebo, (n=2, 1, and 0) in the Pulmicort Respules 0.5 mg, 1 mg, and placebo groups, respectively.

A dose dependent effect on growth was also noted in this 12 week trial. Infants in the placebo arm experienced an average growth of 3.7 cm over 12 weeks compared with 3.5 cm and 3.1 cm in the Pulmicort Respules 0.5 mg and 1 mg arms respectively. This corresponds to estimated mean (95% CI) reductions in 12 week growth velocity between placebo and Pulmicort Respules 0.5 mg of 0.2 cm (-0.6 to 1.0) and between placebo and Pulmicort Respules 1 mg of 0.6 cm (-0.2 to 1.4). These findings support that the use of Pulmicort Respules in infants 6-12 months of age may result in systemic effects and are consistent with findings of growth suppression in other studies with inhaled corticosteroids.

Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. In these studies, the mean reduction in growth velocity was approximately 1 cm/year (range 0.3-1.8 cm/year) and appears to be related to dose and duration of exposure. 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 inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for "catch up" growth following discontinuation of treatment with inhaled corticosteroids has not been adequately studied. The growth of pediatric patients receiving inhaled corticosteroids, including Pulmicort Respules, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of inhaled corticosteroids, including Pulmicort Respules, each patient should be titrated to his/her lowest effective dose.

Geriatric Use

Of the 215 patients in 3 clinical trials of Pulmicort Respules in adult patients, 65 (30%) were 65 years of age or older, while 22 (10%) were 75 years of age or older. No overall differences in safety were observed between these patients and younger patients, and other reported clinical or medical surveillance experience has not identified differences in responses between the elderly and younger patients.

Pulmicort Turbuhaler

General

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.

Pulmicort Turbuhaler 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 Pulmicort Turbuhaler 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 Pulmicort Turbuhaler.

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, Pulmicort Turbuhaler 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 Pulmicort Turbuhaler, Pediatric Use).

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

In clinical trials with Pulmicort Turbuhaler, 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 Pulmicort Turbuhaler therapy, but at times therapy with Pulmicort Turbuhaler 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

For proper use of Pulmicort Turbuhaler and to attain maximum improvement, the patient should read and follow the accompanying Patient's Instructions for Use carefully. In addition, patients being treated with Pulmicort Turbuhaler 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 Pulmicort Turbuhaler 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.

• Pulmicort Turbuhaler is not a bronchodilator and is not intended to treat acute or life-threatening episodes of asthma.

• Pulmicort Turbuhaler must be in the upright position (mouthpiece on top) during loading in order to provide the correct dose. Pulmicort Turbuhaler 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 gripfully 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, Pulmicort Turbuhaler 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 Pulmicort Turbuhaler.

• 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 Turbuhaler. This lack of "sensation" does not indicate that the patient is not receiving benefit from Pulmicort Turbuhaler.

• 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 Pulmicort Turbuhaler, a red mark will appear in the indicator window.

• Pulmicort Turbuhaler 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 Pulmicort Turbuhaler clean and dry at all times.

• Improvement in asthma control following inhalation of Pulmicort Turbuhaler can occur within 24 hours of beginning treatment although maximum benefit may not be achieved for 1-2 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.

• For proper use of Pulmicort Turbuhaler and to attain maximum improvement, the patient should read and follow the accompanying Patient's Instructions for Use.

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 μg/kg/day (approximately 1/2 the maximum recommended daily inhalation dose in adults and children on a μg/m² basis).

In a 104 week oral study in Sprague-Dawley rats, a statistically significant increase in the incidence of gliomas was observed in male rats receiving an oral dose of 50 μg/kg/day (approximately 1/4 the maximum recommended daily inhalation dose on a μg/m² basis); no such changes were seen in male rats receiving oral doses of 10 and 25 μg/kg/day (approximately 1/20 and 1/8 the maximum recommended daily inhalation dose on a μg/m² basis) or in female rats at oral doses up to 50 μg/kg/day (approximately 1/4 the maximum recommended human daily inhalation dose on a μg/m² basis).

Two additional 104 week carcinogenicity studies have been performed with oral budesonide at doses of 50 μg/kg/day (approximately 1/3 the maximum recommended daily inhalation dose in adults and children on a μg/m² basis) in male Sprague-Dawley and Fischer rats. These studies did not demonstrate an increased glioma incidence in budesonide-treated animals as compared with concurrent controls or reference corticosteroid-treated groups (prednisolone and triamcinolone acetonide). Compared with concurrent controls, a statistically significant increase in the incidence of hepatocellular tumors was observed in all three steroid groups (budesonide, prednisolone, triamcinolone acetonide) in these studies.

The mutagenic potential of budesonide was evaluated 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. Budesonide was not mutagenic or clastogenic in any of these tests.

The effect of SC budesonide on fertility and general reproductive performance was studied in rats. At 20 μg/kg/day (approximately 1/8 the maximum recommended daily inhalation dose in adults on a μg/m² basis), decreases in maternal body weight gain, prenatal viability, and viability of the young at birth and during lactation were observed. No such effects were noted at 5 μg/kg (approximately 1/32 the maximum recommended daily inhalation dose in adults on a μg/m² basis).

Pregnancy

Teratogenic Effects, Pregnancy Category B

As with other glucocorticoids, budesonide produced fetal loss, decreased pup weight and skeletal abnormalities at SC doses of 25 μg/kg/day in rabbits (approximately 1/3 the maximum recommended daily inhalation dose in adults on a μg/m² basis) and 500 μg/kg/day in rats (approximately 3 times the maximum recommended daily inhalation dose in adults on a μg/m² basis).

No teratogenic or embryocidal effects were observed in rats when budesonide was administered by inhalation at doses up to 250 μg/kg/day (approximately 2 times the maximum recommended daily inhalation dose in adults on a μg/m² basis).

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.

Studies of pregnant women, however, have not shown that Pulmicort Turbuhaler increases the risk of abnormalities when administered during pregnancy. The results from a large population-based prospective cohort epidemiological study reviewing data from three Swedish registries covering approximately 99% of the pregnancies from 1995-1997 (i.e., Swedish Medical Birth Registry; Registry of Congenital Malformations; Child Cardiology Registry) indicate no increased risk for congenital malformations from the use of inhaled budesonide during early pregnancy. Congenital malformations were studied in 2014 infants born to mothers reporting the use of inhaled budesonide for asthma in early pregnancy (usually 10-12 weeks after the last menstrual period), the period when most major organ malformations occur. The rate of recorded congenital malformations was similar compared to the general population rate (3.8% vs 3.5%, respectively). In addition, after exposure to inhaled budesonide, the number of infants born with orofacial clefts was similar to the expected number in the normal population (4 children vs 3.3, respectively).

These same data were utilized in a second study bringing the total to 2534 infants whose mothers were exposed to inhaled budesonide. In this study, the rate of congenital malformations among infants whose mothers were exposed to inhaled budesonide during early pregnancy was not different from the rate for all newborn babies during the same period (3.6%).

Despite the animal findings, it would appear that the possibility of fetal harm is remote if the drug is used during pregnancy. Nevertheless, because the studies in humans cannot rule out the possibility of harm, Pulmicort Turbuhaler should be used during pregnancy only if clearly needed.

Nonteratogenic Effects

Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully observed.

Nursing Mothers

Corticosteroids are secreted in human milk. Because of the potential for adverse reactions in nursing infants from any corticosteroid, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Actual data for budesonideare lacking.

Pediatric Use

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

In pediatric asthma patients the frequency of adverse events observed with Pulmicort Turbuhaler was similar between the 6-12 year age group (n=172) compared with the 13-17 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 (see PRECAUTIONS, Pulmicort Turbuhaler).

Geriatric Use

One hundred (100) patients 65 years or older were included in the US and non-US controlled clinical trials of Pulmicort Turbuhaler. There were no differences in the safety and efficacy of the drug compared to those seen in younger patients.

Pulmicort Respules

The following adverse reactions were reported in pediatric patients treated with Pulmicort Respules.

The incidence of common adverse reactions is based on three double-blind, placebo-controlled, US clinical trials in which 945 patients, 12 months to 8 years of age, (98 patients ≥12 months and <2 years of age; 225 patients ≥2 and <4 years of age; and 622 patients ≥4 and ≤8 years of age) were treated with Pulmicort Respules (0.25 to 1 mg total daily dose for 12 weeks) or vehicle placebo. The incidence and nature of adverse events reported for Pulmicort Respules was comparable to that reported for placebo. TABLE 1 shows the incidence of adverse events in US controlled clinical trials, regardless of relationship to treatment, in patients previously receiving bronchodilators and/or inhaled corticosteroids. This population included a total of 605 male and 340 female patients.

TABLE 1 Adverse Events With ≥3% Incidence Reported by Patients on Pulmicort Respules     Vehicle Pulmicort Respules Total Daily Dose     Placebo 0.25 mg 0.5 mg 1 mg Adverse Events (n=227) (n=178) (n=223) (n=317) Respiratory System Disorder   Respiratory infection 36% 34% 35% 38%   Rhinitis 9% 7% 11% 12%   Coughing 5% 5% 9% 8% Resistance Mechanism Disorders   Otitis media 11% 12% 11% 9%   Viral infection 3% 4% 5% 3%   Moniliasis 2% 4% 3% 4% Gastrointestinal System Disorders   Gastroenteritis 4% 5% 5% 5%   Vomiting 3% 2% 4% 4%   Diarrhea 2% 4% 4% 2%   Abdominal pain 2% 3% 2% 3% Hearing and Vestibular Disorders   Ear infection 4% 2% 4% 5% Platelet, Bleeding, and Clotting Disorders   Epistaxis 1% 2% 4% 3% Vision Disorders   Conjunctivitis 2% <1% 4% 2% Skin and Appendages Disorders   Rash 3% <1% 4% 2%

TABLE 1 shows all adverse events with an incidence of 3% or more in at least one active treatment group where the incidence was higher with Pulmicort Respules than with placebo.

The following adverse events occurred with an incidence of 3% or more in at least 1 Pulmicort Respules group where the incidence was equal to or less than that of the placebo group: fever, sinusitis, pain, pharyngitis, bronchospasm, bronchitis, and headache.

Incidence 1 to ≤3% (by body system)

The information below includes all adverse events with an incidence of 1 to ≤3%, in at least 1 Pulmicort Respules treatment group where the incidence was higher with Pulmicort Respules than with placebo, regardless of relationship to treatment.

Body as a Whole: Allergic reaction, chest pain, fatigue, flu-like disorder.

Respiratory System: Stridor.

Resistance Mechanisms: Herpes simplex, external ear infection, infection.

Central & Peripheral Nervous System: Dysphonia, hyperkinesia.

Skin & Appendages: Eczema, pustular rash, pruritus.

Hearing & Vestibular: Earache.

Vision: Eye infection.

Psychiatric: Anorexia, emotional lability.

Musculoskeletal System: Fracture, myalgia.

Application Site: Contact dermatitis.

Platelet, Bleeding & Clotting: Purpura.

White Cell and Resistance: Cervical lymphadenopathy.

The incidence of reported adverse events was similar between the 447 Pulmicort Respules-treated (mean total daily dose 0.5 to 1 mg) and 223 conventional therapy-treated pediatric asthma patients followed for 1 year in three open-label studies.

Cases of growth suppression have been reported for inhaled corticosteroids including post-marketing reports for Pulmicort Respules (see PRECAUTIONS, Pulmicort Respules, Pediatric Use).

Less frequent adverse events (<1%) reported in the published literature, long-term, open-label clinical trials, or from marketing experience for inhaled budesonide include: immediate and delayed hypersensitivity reactions including rash, contact dermatitis, angioedema, and bronchospasm; symptoms of hypocorticism and hypercorticism; psychiatric symptoms including depression, aggressive reactions, irritability, anxiety, and psychosis; and bone disorders including avascular necrosis of the femoral head and osteoporosis.

Pulmicort Turbuhaler

The following adverse reactions were reported in patients treated with Pulmicort Turbuhaler.

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 Pulmicort Turbuhaler (200-800 μg twice daily for 12-20 weeks) or placebo.

TABLE 2 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 2 Adverse Events With ≥3% Incidence Reported by Patients on Pulmicort Turbuhaler       Pulmicort Turbuhaler     Placebo 200 μg* 400 μg* 800 μg* Adverse Event n=284 n=286 n=289 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

* Twice daily.

TABLE 2 includes all events (whether considered drug-related or non drug-related by the investigators) that occurred at a rate of ≥3% in any one Pulmicort Turbuhaler group and were more common than in the placebo group. In considering these data, the increased average duration of exposure for Pulmicort Turbuhaler patients should be taken into account.

The following other adverse events occurred in these clinical trials using Pulmicort Turbuhaler 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 Pulmicort Turbuhaler 400 μg twice daily (n=53) and 800 μg 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 Pulmicort Turbuhaler group and which occurred more frequently with Pulmicort Turbuhaler than placebo are shown below (% Pulmicort Turbuhaler and % placebo). In considering these data, the increased average duration of exposurefor Pulmicort Turbuhaler patients (78 days for Pulmicort Turbuhaler 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%).

Patients Receiving Pulmicort Turbuhaler Once Daily

The adverse event profile of once-daily administration of Pulmicort Turbuhaler 200 and 400 μg, 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 Pulmicort Turbuhaler 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 Pulmicort Turbuhaler (at 100, 200 and 400 μg 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.

Pulmicort Respules

The potential for acute toxic effects following overdose of Pulmicort Respules is low. If inhaled corticosteroids are used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism or growth suppression may occur (see PRECAUTIONS, Pulmicort Respules).

In mice the minimal lethal inhalation dose was 100 mg/kg (approximately 410 or 120 times, respectively, the maximum recommended daily inhalation dose in adults or children on a mg/m² basis). In rats there were no deaths at an inhalation dose of 68 mg/kg (approximately 550 or 160 times, respectively, the maximum recommended daily inhalation dose in adults or children on a mg/m² basis). In mice the minimal oral lethal dose was 200 mg/kg (approximately 810 or 240 times, respectively, the maximum recommended daily inhalation dose in adults or children on a mg/m² basis). In rats, the minimal oral lethal dose was less than 100 mg/kg (approximately 810 or 240 times, respectively, the maximum recommended daily inhalation dose in adults or children on a mg/m² basis).

Pulmicort Turbuhaler

The potential for acute toxic effects following overdose of Pulmicort Turbuhaler is low. If used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism may occur (see PRECAUTIONS, Pulmicort Turbuhaler). Pulmicort Turbuhaler at twice the highest recommended dose (3200 μg 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 μg/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 μg/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 μg/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 based on a μg/m² basis).

Pulmicort Respules

Pulmicort Respules is indicated for use in asthmatic patients 12 months to 8 years of age. Pulmicort Respules should be administered by the inhaled route via jet nebulizer connected to an air compressor. Individual patients will experience a variable onset and degree of symptom relief. Improvement in asthma control following inhaled administration of Pulmicort Respules can occur within 2-8 days of initiation of treatment, although maximum benefit may not be achieved for 4-6 weeks. The safety and efficacy of Pulmicort Respules when administered in excess of recommended doses have not been established. In all patients, it is desirable to downward-titrate to the lowest effective dose once asthma stability is achieved. The recommended starting dose and highest recommended dose of Pulmicort Respules, based on prior asthma therapy, are listed in TABLE 3.

TABLE 3 Previous Therapy Recommended Starting Dose Highest Recommended Dose Bronchodilators alone 0.5 mg total daily dose administered either once or twice daily in divided doses 0.5 mg total daily dose Inhaled corticosteroids 0.5 mg total daily dose administered either once or twice daily in divided doses 1 mg total daily dose Oral corticosteroids 1 mg total daily dose administered either as 0.5 mg twice daily or 1 mg once daily 1 mg total daily dose

In symptomatic children not responding to non-steroidal therapy, a starting dose of 0.25 mg once daily of Pulmicort Respules may also be considered.

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

Patients Not Receiving Systemic (oral) Corticosteroids

Patients who require maintenance therapy of their asthma may benefit from treatment with Pulmicort Respules at the doses recommended above. Once the desired clinical effect is achieved, consideration should be given to tapering to the lowest effective dose. For the patients who do not respond adequately to the starting dose, consideration should be given to administering the total daily dose as a divided dose, if a once-daily dosing schedule was followed. If necessary, higher doses, up to the maximum recommended doses, may provide additional asthma control.

Patients Maintained on Chronic Oral Corticosteroids

Initially, Pulmicort Respules should be used concurrently with the patient's usual maintenance dose of systemic corticosteroid. After approximately 1 week, gradual withdrawal of the systemic corticosteroid may be initiated by reducing the daily or alternate daily dose. Further incremental reductions may be made after an interval of 1 or 2 weeks, depending on the response of the patient. Generally, these decrements should not exceed 25% of the prednisone dose 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, Pulmicort Respules). 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 Pulmicort Respules 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.

A Pari-LC-Jet Plus Nebulizer (with face mask or mouthpiece) connected to a Pari Master compressor was used to deliver Pulmicort Respules to each patient in 3 US controlled clinical studies. The safety and efficacy of Pulmicort Respules delivered by other nebulizers and compressors have not been established.

Pulmicort Respules should be administered via jet nebulizer connected to an air compressor with an adequate air flow, equipped with a mouthpiece or suitable face mask. Ultrasonic nebulizers are not suitable for the adequate administration of Pulmicort Respules and, therefore, are NOT recommended.

The effects of mixing Pulmicort Respules with other nebulizable medications have not been adequately assessed. Pulmicort Respules should be administered separately in the nebulizer (see PRECAUTIONS, Pulmicort Respules, Information for the Patient).

Directions for Use

Illustrated Patient's Instructions for Use accompany each package of Pulmicort Respules.

Pulmicort Turbuhaler

Pulmicort Turbuhaler 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, Pulmicort Turbuhaler has a relatively rapid onset of action for an inhaled corticosteroid. Improvement in asthma control following inhaled administration of Pulmicort Turbuhaler 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 Pulmicort Turbuhaler when administered in excess of recommended doses have not been established.

The recommended starting dose and the highest recommended dose of Pulmicort Turbuhaler, 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 μg twice daily 400 μg twice daily   Inhaled corticosteroids* 200-400 μg twice daily 800 μg twice daily   Oral corticosteroids 400-800 μg twice daily 800 μg twice daily Children   Bronchodilators alone 200 μg twice daily 400 μg twice daily   Inhaled corticosteroids* 200 μg twice daily 400 μg twice daily   Oral corticosteroids The highest recommended dose in children is 400 μg twice daily

* In patients with mild to moderate asthma who are well controlled on inhaled corticosteroids, dosing with Pulmicort Turbuhaler 200 or 400 μg once daily may be considered. Pulmicort Turbuhaler can be administered once daily either in the morning or in the evening.

If the once-daily treatment with Pulmicort Turbuhaler 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, Pulmicort Turbuhaler should be used concurrently with the patient's usual maintenance dose of systemic corticosteroid. After approximately 1 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, Pulmicort Turbuhaler). 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 Pulmicort Turbuhaler 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 Pulmicort Turbuhaler 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.

Directions for Use

Illustrated Patient's Instructions for Use accompany each package of Pulmicort Turbuhaler.

Budesonide is a synthetic corticosteroid having potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro and animal models, budesonide has approximately a 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 glucocorticoid 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 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 mediated inflammation.

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.

Pharmacokinetics

The pharmacokinetics of budesonide have been studied following nasal, oral and IV administration. Budesonide is relatively well absorbed after both inhalation and oral administration, and is rapidly metabolized into metabolites with low corticosteroid potency. The clinical activity of Rhinocort Aquanasal spray is therefore believed to be due to the parent drug, budesonide. In vitro studies indicate that the two epimeric forms of budesonide do not interconvert.

Absorption

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

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. 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 (16α-hydroxyprednisolone and 6β-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 glucocorticoid 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 radiolabeled 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 16α-hydroxyprednisolone (24%) and 6β-hydroxybudesonide (5%). An additional 34% of the radioactivity recovered in the urine was identified as conjugates.

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, 2-3 hours, was similar for both epimers and it appeared to be independent of dose.

Special Populations

Geriatric

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

Pediatric

After administration of Rhinocort Aqua nasal spray, 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.

Gender

No specific pharmacokinetic study has been conducted to evaluate the effect of gender on budesonide pharmacokinetics. However, following administration of 400 μg Rhinocort Aqua nasal spray 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 relevance of this finding to intranasally administered budesonide has not been established.

Pharmacodynamics

A 3 week clinical study in seasonal rhinitis, comparing Rhinocort nasal inhaler, orally ingested budesonide, and placebo in 98 patients with allergic rhinitis due to birch pollen, demonstrated that the therapeutic effect of Rhinocort nasal inhaler can be attributed to the topical effects of budesonide.

The effects of Rhinocort Aqua nasal spray on adrenal function have been evaluated in several clinical trials. In a 4 week clinical trial, 61 adult patients who received 256 μg daily of Rhinocort Aqua nasal spray demonstrated no significant differences from patients receiving placebo in plasma cortisollevels 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 μg daily. Similar results were seen in a study of 150 children and adolescents aged 6-17 with perennial rhinitis who were treated with 256 μg daily for up to 12 months.

After treatment with the recommended maximal daily dose of Rhinocort Aqua (256 μg) for 7 days, there was a small, but statistically significant decrease in the area under the plasma cortisol-time curve over 24 hours [AUC(0-24h)] in healthy adult volunteers.

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