budesonide 0.5 MG per 2 ML Inhalant Suspension
Generic Name: BUDESONIDE
Brand Name: Budesonide
- Substance Name(s):
- BUDESONIDE
DRUG INTERACTIONS
7 • Strong cytochrome P4503A4 inhibitors (e.g., ritonavir): Use with caution.
May cause increased systemic corticosteroid effects.
(5.12, 7.1) 7.1 Inhibitors of Cytochrome P4503A4 The main route of metabolism of corticosteroids, including budesonide, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4).
After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased.
Concomitant administration of a CYP3A4 inhibitor may inhibit the metabolism of, and increase the systemic exposure to, budesonide.
Caution should be exercised when considering the coadministration of budesonide inhalation suspension with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [seeWARNINGS AND PRECAUTIONS (5.12) andCLINICAL PHARMACOLOGY, Pharmacokinetics (12.3)].
OVERDOSAGE
10 The potential for acute toxic effects following overdose of budesonide inhalation suspension 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 WARNINGS AND PRECAUTIONS, Hypercorticism and Adrenal Suppression (5.6)].
In mice, the minimal lethal inhalation dose was 100 mg/kg (approximately 410 and 120 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mg/m2 basis).
In rats there were no deaths at an inhalation dose of 68 mg/kg (approximately 550 and 160 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mg/m2 basis).
In mice, the minimal oral lethal dose was 200 mg/kg (approximately 810 and 240 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mg/m2 basis).
In rats, the minimal oral lethal dose was less than 100 mg/kg (approximately 810 and 240 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mg/m2 basis).
DESCRIPTION
11 Budesonide, the active component of budesonide inhalation suspension, 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 inhalation suspension is provided as a mixture of two epimers (22R and 22S).
The molecular formula of budesonide is C25H34O6 and its molecular weight is 430.5.
Its structural formula is: 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 x 103.
Budesonide inhalation suspension is a sterile suspension for inhalation via jet nebulizer and contains the active ingredient budesonide (micronized), and the inactive ingredients: citric acid monohydrate, disodium edetate, polysorbate 80, sodium chloride, sodium citrate dihydrate and water for injection.
Three dose strengths are available in single-dose ampules: 0.25 mg, 0.5 mg, and 1 mg per 2 mL ampule.
For budesonide inhalation suspension, 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/Pari Master 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.
Budesonide inhalation suspension should be administered from jet nebulizers at adequate flow rates, via face masks or mouthpieces [see DOSAGE AND ADMINISTRATION (2)].
Structure
CLINICAL STUDIES
14 Three double-blind, placebo-controlled, parallel group, randomized U.S.
clinical trials of 12-weeks duration each were conducted in 1018 pediatric patients, 6 months to 8 years of age, 657 males and 361 females (798 Caucasians, 140 Blacks, 56 Hispanics, 3 Asians, 21 Others) with persistent asthma of varying disease duration (2 to 107 months) and severity.
Doses of 0.25 mg, 0.5 mg, 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 budesonide inhalation suspension to patients in the 3 U.S.
controlled clinical trials.
The co-primary endpoints were nighttime and daytime asthma symptom scores (0 to 3 scale).
Improvements were addressed in terms of the primary efficacy variables of changes from baseline to the double-blind treatment period in nighttime and daytime asthma symptom scores (scale 0 to 3) as recorded in the patient diaries.
Baseline was defined as the mean of the last seven days prior to randomization).
The double-blind treatment period was defined as the mean over 12 week treatment period.
Each of the five doses discussed below were studied in one or two, but not all three of the U.S.
studies.
Results of the 3 controlled clinical trials for recommended dosages of budesonide inhalation suspension (0.25 mg to 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.
Statistically significant decreases in nighttime and daytime symptom scores of asthma were observed at budesonide inhalation suspension doses of 0.25 mg once daily (one study), 0.25 mg twice daily, and 0.5 mg twice daily compared to placebo.
Use of budesonide inhalation suspension resulted in statistically significant decreases in 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 budesonide inhalation suspension occurred across gender and age.
Statistically significant reductions in the need for bronchodilator therapy were also observed at all the doses of budesonide inhalation suspension studied.
Improvements in lung function were associated with budesonide inhalation suspension in the subgroup of patients capable of performing lung function testing.
Statistically significant increases were seen in FEV1 [budesonide inhalation suspension 0.5 mg once daily and 1 mg once daily (one study); 0.5 mg twice daily] and morning PEF [budesonide inhalation suspension 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 to 3 scale) of asthma was observed within 2 to 8 days, although maximum benefit was not achieved for 4 to 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 budesonide inhalation suspension at doses of 0.25 mg, 0.5 mg, 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 to 1.34) who were not well controlled by bronchodilators alone.
The changes from baseline to Weeks 0 to 12 in nighttime asthma symptom scores are shown in Figure 1.
Nighttime asthma symptom scores showed statistically significant decreases in the patients treated with budesonide inhalation suspension compared to placebo.
Similar decreases were also observed for daytime asthma symptom scores.
Changes from baseline to the double-blind phase for the budesonide treatment groups compared to placebo were made using analysis of variance techniques.
The model included terms for the respective changes from baseline as the dependent variable and terms for treatment, center and treatment by center interaction as exploratory variables.
(See Figures 1 to 3).
Figure 1: A 12-Week Trial in Pediatric Patients Not on Inhaled Corticosteroid Therapy Prior to Study Entry.
Nighttime Asthma Change from Baseline Patients Previously Maintained on Inhaled Corticosteroids The efficacy of budesonide inhalation suspension at doses of 0.25 mg and 0.5 mg twice daily was evaluated in 133 pediatric asthma patients, 4 to 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 to 1.18; mean baseline dose of beclomethasone dipropionate of 265 mcg/day, ranging between 42 to 1008 mcg/day; mean baseline dose of triamcinolone acetonide of 572 mcg/day, ranging between 200 to 1200 mcg/day).
The changes from baseline to Weeks 0 to12 in nighttime asthma symptom scores are shown in Figure 2.
Nighttime asthma symptom scores showed statistically significant decreases in patients treated with budesonide inhalation suspension compared to placebo.
Similar decreases were also observed for daytime asthma symptom scores.
Statistically significant increases in FEV1 compared to placebo were observed with budesonide inhalation suspension at a dose of 0.5 mg twice daily and in morning PEF for both doses (0.25 mg and 0.5 mg twice daily).
Figure 2: A 12-Week Trial in Pediatric Patients Previously Maintained on Inhaled Corticosteroid Therapy Prior to Study Entry.
Nighttime Asthma Change from Baseline Patients Receiving Once-Daily or Twice-Daily Dosing The efficacy of budesonide inhalation suspension 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 to 1.31).
Approximately 70% were not previously receiving inhaled corticosteroids.
The changes from baseline to Weeks 0 to 12 in nighttime asthma symptom scores are shown in Figure 3.
Budesonide inhalation suspension at doses of 0.25 mg and 0.5 mg twice daily, and 1 mg once daily, demonstrated statistically significant decreases in nighttime asthma symptom scores compared to placebo.
Similar decreases were also observed for daytime asthma symptom scores.
Budesonide inhalation suspension at a dose of 0.5 mg twice daily resulted in statistically significant increases compared to placebo in FEV1, and at doses of 0.25 mg and 0.5 mg twice daily and 1 mg once daily statistically significant increases in morning PEF.
The evidence supports the efficacy of the same nominal dose of budesonide inhalation suspension 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).
Figure 3: A 12-Week Trial in Pediatric Patients Either Maintained on Bronchodilators Alone or Inhaled Corticosteroid Therapy Prior to Study Entry.
Nighttime Asthma Change from Baseline Figure 1 figure 2 Figure 3
HOW SUPPLIED
16 /STORAGE AND HANDLING Budesonide inhalation suspension is supplied in sealed aluminum foil envelopes containing one plastic strip of five single-dose ampules together with patient instructions for use.
There are 30 ampules in a carton (6 pouches x 5 single-dose ampules).
Each single-dose ampule contains 2 mL of sterile liquid suspension.
Budesonide inhalation suspension is available in three strengths, each containing 2 mL: NDC # Strength 68788-6796-3 0.5 mg/2 mL Budesonide inhalation suspension should be stored upright at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature] and protected from light.
When an envelope has been opened, the shelf life of the unused ampules is 2 weeks when protected.
After opening the aluminum foil envelope, the unused ampules should be returned to the aluminum foil envelope to protect them from light.
Any opened ampule must be used promptly.
Gently shake the ampule using a circular motion before use.
Keep out of reach of children.
Do not freeze.
GERIATRIC USE
8.5 Geriatric Use Of the 215 patients in 3 clinical trials of budesonide inhalation suspension 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.
DOSAGE FORMS AND STRENGTHS
3 Budesonide inhalation suspension is available in three strengths, each containing 2 mL: 0.25 mg/2 mL, 0.5 mg/2 mL, and 1 mg/2 mL.Budesonide inhalation suspension is supplied in sealed aluminum foil envelopes containing one plastic strip of five single-dose ampules together with patient instructions for use.
There are 30 ampules in a carton.
Each single-dose ampule contains 2 mL of sterile liquid suspension.
Inhalation suspension: 0.25 mg/2mL, 0.5 mg/2mL, 1 mg/2mL (3)
MECHANISM OF ACTION
12.1 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 clinical significance of these findings is unknown.
The activity of budesonide inhalation suspension is due to the parent drug, budesonide.
In glucocorticoid receptor affinity studies, the 22R form was two times as active as the 22S epimer.
In vitro studies indicated that the two forms of budesonide do not interconvert.
The precise mechanism of corticosteroid actions on inflammation in asthma is not well known.
Inflammation is an important component in the pathogenesis of asthma.
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 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 to 95%) and the low potency of metabolites (see below).
INDICATIONS AND USAGE
1 Budesonide inhalation suspension is an inhaled corticosteroid indicated for: • Maintenance treatment of asthma and as prophylactic therapy in children 12 months to 8 years of age (1.1) Important Limitations of Use: Not indicated for the relief of acute bronchospasm (1.1) 1.1 Maintenance Treatment of Asthma Budesonide inhalation suspension is indicated for the maintenance treatment of asthma and as prophylactic therapy in children 12 months to 8 years of age.
Important Limitations of Use: • Budesonide inhalation suspension is NOT indicated for the relief of acute bronchospasm.
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness in children six months to 12 months of age has been evaluated but not established.
Safety and effectiveness in children 12 months to 8 years of age have been established [see CLINICAL PHARMACOLOGY, Pharmacodynamics (12.2), and ADVERSE REACTIONS, Clinical Trials Experience (6.1)].
A 12-week study in 141 pediatric patients 6 to 12 months of age with mild to moderate asthma or recurrent/persistent wheezing was conducted.
All patients were randomized to receive either 0.5 mg or 1 mg of budesonide inhalation suspension 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 budesonide inhalation suspension versus placebo.
However, on an individual basis, 7 patients in this study (6 in the budesonide inhalation suspension 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, Pharmacodynamics (12.2)] .
Pneumonia was observed more frequently in patients treated with budesonide inhalation suspension than in patients treated with placebo, (N = 2, 1, and 0) in the budesonide inhalation suspension 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 budesonide inhalation suspension 0.5 mg and 1 mg arms respectively.
This corresponds to estimated mean (95% CI) reductions in 12-week growth velocity between placebo and budesonide inhalation suspension 0.5 mg of 0.2 cm (-0.6 to 1) and between placebo and budesonide inhalation suspension 1 mg of 0.6 cm (-0.2 to 1.4).
These findings support that the use of budesonide inhalation suspension in infants 6 to 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 one centimeter per year (range 0.3 to 1.8 cm per 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 orally inhaled corticosteroids, including the impact on final adult height, are unknown.
The potential for “catch up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied.
In a study of asthmatic children 5 to 12 years of age, those treated with budesonide administered via a dry powder inhaler 200 mcg twice daily (n=311) had a 1.1-centimeter reduction in growth compared with those receiving placebo (n=418) at the end of one year; the difference between these two treatment groups did not increase further over three years of additional treatment.
By the end of four years, children treated with the budesonide dry powder inhaler and children treated with placebo had similar growth velocities.
Conclusions drawn from this study may be confounded by the unequal use of corticosteroids in the treatment groups and inclusion of data from patients attaining puberty during the course of the study.
The growth of pediatric patients receiving inhaled corticosteroids, including budesonide inhalation suspension, 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 and benefits associated with alternative therapies.
To minimize the systemic effects of inhaled corticosteroids, including budesonide inhalation suspension, each patient should be titrated to his/her lowest effective dose [see DOSAGE AND ADMINISTRATION (2)andWARNINGS AND PRECAUTIONS (5.8)]
PREGNANCY
8.1 Pregnancy Teratogenic effects Pregnancy Category B Studies of pregnant women, 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 to 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 to 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).
As with other corticosteroids, budesonide was teratogenic and embryocidal in rabbits and rats.
Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at subcutaneous doses of 25 mcg/kg in rabbits (less than the maximum recommended daily inhalation dose in adults on a mcg/m2 basis) and 500 mcg/kg in rats (approximately 4 times the maximum recommended daily inhalation dose in adults on a mcg/m2 basis).
In another study in rats, no teratogenic or embryocidal effects were seen at inhalation doses up to 250 mcg/kg (approximately 2 times the maximum recommended daily inhalation dose in adults on a mcg/m2 basis).
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, budesonide inhalation suspension should be used during pregnancy only if clearly needed.
As with other corticosteroids, budesonide was teratogenic and embryocidal in rabbits and rats.
Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at a subcutaneous dose in rabbits that was approximately 0.4 times the maximum recommended daily inhalation dose in adults on a mcg/m2 basis and at subcutaneous dose that was approximately 4 times the maximum recommended daily inhalation dose in adults on a mcg/m2 basis.
In another study in rats, no teratogenic or embryocidal effects were seen at inhalation doses up to approximately 2 times the maximum recommended daily inhalation dose in adults on a mcg/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.
Nonteratogenic effects Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy.
Such infants should be carefully observed.
NUSRING MOTHERS
8.3 Nursing Mothers Budesonide, like other corticosteroids, is secreted in human milk.
Data with budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother [see CLINICAL PHARMACOLOGY, Pharmacokinetics (12.3), and USE IN SPECIFIC POPULATIONS, Nursing Mothers (8.3)] .
No studies have been conducted in breastfeeding women with budesonide inhalation suspension; however, the dose of budesonide available to the infant in breast milk, as a percentage of the maternal dose, would be expected to be similar.
Budesonide inhalation suspension should be used in nursing women only if clinically appropriate.
Prescribers should weigh the known benefits of breastfeeding for the mother and the infant against the potential risks of minimal budesonide exposure in the infant.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS •Localized infections: Candida albicansinfection of the mouth and throat may occur.
Monitor patients periodically for signs of adverse effects on the oral cavity.
Advise patients to rinse the mouth following inhalation.
(5.1) •Deterioration of disease and acute asthma episodes: Do not use for the relief of acute bronchospasm.
(5.2) •Hypersensitivity reactions: anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of budesonide inhalation suspension.
Discontinue budesonide inhalation suspension if such reactions occur (5.3) •Immunosuppression: Potential worsening of infections (e.g., existing tuberculosis, fungal, bacterial, viral, or parasitic infection; or ocular herpes simplex).
Use with caution in patients with these infections.
More serious or even fatal course of chickenpox or measles can occur in susceptible patients.
(5.4) •Transferring patients from systemic corticosteroids: Risk of impaired adrenal function when transferring from oral steroids.
Taper patients slowly from systemic corticosteroids if transferring to budesonide inhalation suspension (5.5) •Hypercorticism and adrenal suppression: May occur with very high dosages or at the regular dosage in susceptible individuals.
If such changes occur, reduce budesonide inhalation suspension slowly.
(5.6) •Reduction in bone mineral density with long term administration.
Monitor patients with major risk factors for decreased bone mineral content.
(5.7) •Effects on growth: Monitor growth of pediatric patients.
(5.8) •Glaucoma and cataracts: Close monitoring is warranted.
(5.9) •Paradoxical bronchospasm: Discontinue Budesonide inhalation suspension and institute alternative therapy if paradoxical bronchospasm occurs.
(5.10) •Eosinophilic conditions and Churg-Strauss syndrome: Be alert to eosinophilic conditions.
(5.11) 5.1 Local Effects In clinical trials with budesonide inhalation suspension, localized infections with Candida albicansoccurred in the mouth and pharynx in some patients.
The incidences of localized infections of Candida albicanswere similar between the placebo and budesonide inhalation suspension treatment groups.
If these infections develop, they may require treatment with appropriate local or systemic antifungal therapy and/or discontinuance of treatment with budesonide inhalation suspension.
Patients should rinse the mouth after inhalation of budesonide inhalation suspension.
5.2 Deterioration of Disease and Acute Asthma Episodes Budesonide inhalation suspension is not a bronchodilator and is not indicated for the rapid relief of acute bronchospasm or other acute episodes of asthma.
Patients should be instructed to contact their physician immediately if episodes of asthma not responsive to their usual doses of bronchodilators occur during the course of treatment with budesonide inhalation suspension.
During such episodes, patients may require therapy with oral corticosteroids 5.3 Hypersensitivity Reactions Including Anaphylaxis Hypersensitivity reactions including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of budesonide inhalation suspension.
Discontinue budesonide inhalation suspension if such reactions occur [see CONTRAINDICATIONS ( 4 )].
5.4 Immunosuppression Patients who are on drugs that 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 children or adults using corticosteroids.
In children or adults who have not had these diseases, or been properly immunized, particular care should be taken to avoid exposure.
How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known.
The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known.
If exposed to chicken pox, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated.
If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated.
(See the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents may be considered.
The clinical course of chicken pox or measles infection in patients on inhaled corticosteroids has not been studied.
However, a clinical study has examined the immune responsiveness of asthma patients 12 months to 8 years of age who were treated with budesonide inhalation suspension.
An open-label non-randomized clinical study examined the immune responsiveness of varicella vaccine in 243 asthma patients 12 months to 8 years of age who were treated with budesonide inhalation suspension 0.25 mg to 1 mg daily (n=151) or noncorticosteroid asthma therapy (n=92) (ie, beta2-agonists, leukotriene receptor antagonists, cromones).
The percentage of patients developing a seroprotective antibody titer of ≥ 5 (gpELISA value) in response to the vaccination was similar in patients treated with budesonide inhalation suspension (85%) compared to patients treated with non-corticosteroid asthma therapy (90%).
No patient treated with budesonide inhalation suspension developed chicken pox as a result of vaccination.
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.
5.5 Transferring Patients from Systemic Corticosteroid Therapy 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 hypothalamic-pituitary-adrenal (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 budesonide inhalation suspension may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticosteroid 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 medical identification card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.
Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to budesonide inhalation suspension.
Initially, budesonide inhalation suspension should be used concurrently with the patient’s usual maintenance dose of systemic corticosteroid.
After approximately one 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 one or two 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.
Lung function (FEV1 or AM PEF), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids.
In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.
Transfer of patients from systemic corticosteroid therapy to budesonide inhalation suspension may unmask allergic or other immunologic conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, eosinophilic conditions, eczema, and arthritis [see DOSAGE AND ADMINISTRATION ( 2 )].
During withdrawal from oral corticosteroids, patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.
5.6 Hypercorticism and Adrenal Suppression Budesonide inhalation suspension, will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone.
Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing budesonide inhalation suspension.
Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with budesonide inhalation suspension 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 (including adrenal crisis) may appear in a small number of patients, particularly when budesonide is administered at higher than recommended doses over prolonged periods of time.
If such effects occur, the dosage of budesonide inhalation suspension should be reduced slowly, consistent with accepted procedures for tapering of systemic corticosteroids and for management of asthma.
5.7 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids.
The clinical significance of small changes in BMD with regard to long-term outcomes is unknown.
Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants and corticosteroids), should be monitored and treated with established standards of care.
5.8 Effects on Growth Orally inhaled corticosteroids, including budesonide, may cause a reduction in growth velocity when administered to pediatric patients.
Monitor the growth of pediatric patients receiving budesonide inhalation suspension routinely (e.g., via stadiometry).
To minimize the systemic effects of orally inhaled corticosteroids, including budesonide inhalation suspension, each patient should be titrated to his/her lowest effective dose [see USE IN SPECIFIC POPULATIONS, Pediatric Use (8.4)].
5.9 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported following the long-term administration of inhaled corticosteroids, including budesonide.
Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.
5.10 Paradoxical Bronchospasm and Upper Airway Symptoms As with other inhaled asthma medications, bronchospasm, with an immediate increase in wheezing, may occur after dosing.
If acute bronchospasm occurs following dosing with budesonide inhalation suspension, it should be treated immediately with a fast-acting inhaled bronchodilator.
Treatment with budesonide inhalation suspension should be discontinued and alternate therapy instituted.
5.11 Eosinophilic Conditions and Churg-Strauss Syndrome In rare cases, patients on inhaled corticosteroids may present with systemic eosinophilic conditions.
Some of these patients have clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroids therapy.
These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of inhaled corticosteroids.
Healthcare providers should be alert to eosinophilia, vasculitis rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients.
A causal relationship between budesonide and these underlying conditions has not been established.
5.12 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of budesonide inhalation suspension with ketoconazole, and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to budesonide may occur [see DRUG INTERACTIONS (7.1) and CLINICAL PHARMACOLOGY, Clinical Pharmacokinetics (12.3) ].
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION 17.1 Administration with a Jet Nebulizer Patients should be advised that budesonide inhalation suspension should be administered with a jet nebulizer connected to a compressor with an adequate air flow, equipped with a mouthpiece or suitable face mask.
Ultrasonic nebulizers are not suitable for the adequate administration of budesonide inhalation suspension and, therefore, are not recommended.
The effects of mixing budesonide inhalation suspension with other nebulizable medications have not been adequately assessed.
Budesonide inhalation suspension should be administered separately in the nebulizer [see DOSAGE AND ADMINISTRATION ( 2 )].
17.2 Oral Candidiasis Patients should be advised that localized infections with Candida albicansoccurred 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 therapy with budesonide inhalation suspension, but at times therapy with budesonide inhalation suspension may need to be temporarily interrupted under close medical supervision.
Rinsing the mouth after inhalation is advised [see WARNINGS AND PRECAUTIONS ( 5.1)].
17.3 Not for Acute Symptoms Budesonide inhalation suspension is not meant to relieve acute asthma symptoms and extra doses should not be used for that purpose.
Acute symptoms should be treated with an inhaled, short-acting beta2-agonist such as albuterol.
(The healthcare professional should provide that patient with such medication and instruct the patient in how it should be used.) Patients should be instructed to notify their healthcare professional immediately if they experience any of the following: •Decreasing effectiveness of inhaled, short-acting beta2-agonists •Need for more inhalations than usual of inhaled, short-acting beta2-agonists •Significant decrease in lung function as outlined by the physician Patients should not stop therapy with budesonide inhalation suspension without physician/provider guidance since symptoms may recur after discontinuation [see WARNINGS AND PRECAUTIONS (5.2 )].
17.4 Hypersensitivity including Anaphylaxis Hypersensitivity reactions including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of budesonide inhalation suspension.
Discontinue budesonide inhalation suspension if such reactions occur [see CONTRAINDICATIONS (4); WARNING AND PRECAUTIONS (5.3)] .
17.5 Immunosuppression Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay.
If exposure to such a person occurs, and the child has not had chicken pox or been properly vaccinated, a physician should be consulted without delay.
Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex [see WARNINGS AND PRECAUTIONS ( 5.4)].
17.6 Hypercorticism and Adrenal Suppression Patients should be advised that budesonide inhalation suspension may cause systemic corticosteroid effects of hypercorticism and adrenal suppression.
Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids.
Patients should taper slowly from systemic corticosteroids if transferring to budesonide inhalation suspension [seeWARNINGS AND PRECAUTIONS (5.6 )].
17.7 Reduction in Bone Mineral Density Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk [see WARNINGS AND PRECAUTIONS (5.7)].
17.8 Reduced Growth Velocity Patients should be informed that orally inhaled corticosteroids, including budesonide inhalation suspension, may cause a reduction in growth velocity when administered to pediatric patients.
Healthcare professionals should closely follow the growth of children and adolescents taking corticosteroids by any route [seeWARNINGS AND PRECAUTIONS (5.8)].
17.9 Ocular Effects Long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); regular eye examinations should be considered [see WARNINGS AND PRECAUTIONS (5.9 )].
17.10 Use Daily Patients should be advised to use budesonide inhalation suspension at regular intervals once or twice a day, since its effectiveness depends on regular use.
Maximum benefit may not be achieved for 4 to 6 weeks or longer after starting treatment.
If symptoms do not improve in that time frame or if the condition worsens, patients should be instructed to contact their healthcare professional.
17.11 FDA-Approved Patient Labeling See accompanying Patient Information and Instructions for Use.
DOSAGE AND ADMINISTRATION
2 The recommended starting dose and highest recommended dose of budesonide inhalation suspension, based on prior asthma therapy, are listed in the following table.
Previous Therapy Recommended Starting Dose Highest Recommended Dose Bronchodilators alone 0.5 mg total daily dose administered either once daily or twice daily in divided doses 0.5 mg total daily dose Inhaled Corticosteroids 0.5 mg total daily dose administered either once daily 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 Recommended dosing based on previous therapy (2).
Start with the lowest recommended dose: •Bronchodilators alone: 0.5 mg once daily or 0.25 mg twice daily •Inhaled corticosteroids: 0.5 mg once daily or 0.25 mg twice daily up to 0.5 mg twice daily •Oral corticosteroids: 0.5 mg twice daily or 1 mg once daily •In symptomatic children not responding to non-steroidal therapy, a starting dose of 0.25 mg once daily may be considered.
•If once-daily treatment does not provide adequate control, the total daily dose should be increased and/or administered as a divided dose.
Once asthma stability is achieved, titrate the dose downwards.
•For inhalation use via compressed air driven jet nebulizers only (not for use with ultrasonic devices).
Not for injection.
(2.2) 2.1 Dosing Recommendations Dosing recommendations based on previous therapy are as follows: •Bronchodilators alone: 0.5 mg once daily or 0.25 mg twice daily •Inhaled corticosteroids: 0.5 mg once daily or 0.25 mg twice daily up to 0.5 mg twice daily •Oral corticosteroids: 0.5 mg twice daily or 1 mg once daily In symptomatic children not responding to non-steroidal therapy, a starting dose of 0.25 mg once daily may be considered.
If once-daily treatment does not provide adequate control, the total daily dose should be increased and/or administered as a divided dose.
In all patients, it is desirable to downward-titrate to the lowest effective dose once asthma stability is achieved.
2.2 Directions for Use Budesonide inhalation suspension 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 budesonide inhalation suspension and, therefore, are NOT recommended.
The effects of mixing budesonide inhalation suspension with other nebulizable medications have not been adequately assessed.
Budesonide inhalation suspension should be administered separately in the nebulizer [see PATIENT COUNSELING INFORMATION , Administration with a jet nebulizer ( 17.1 )].
A Pari-LC-Jet Plus Nebulizer (with face mask or mouthpiece) connected to a Pari Master compressor was used to deliver budesonide inhalation suspension to each patient in 3 U.S.
controlled clinical studies.
The safety and efficacy of budesonide inhalation suspension delivered by other nebulizers and compressors have not been established.