Pulmicort Flexhaler 90 MCG/INHAL Dry Powder Inhaler, 60 ACTUAT
DRUG INTERACTIONS
7 • Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Use with caution.
May cause increased systemic corticosteroid effects.
(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 CYP3A4 may inhibit the metabolism of, and increase the systemic exposure to, budesonide.
Caution should be exercised when considering the co-administration of PULMICORT FLEXHALER with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.7) ].
OVERDOSAGE
10 The potential for acute toxic effects following overdose of PULMICORT FLEXHALER is low.
If used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism may occur [see Warnings and Precautions, Hypercorticism and Adrenal Suppression (5.6) ].
Another budesonide-containing dry powder inhaler at 3200 mcg 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 280 times the maximum recommended daily inhalation dose in adults and approximately 330 times the maximum recommended daily inhalation dose in children 6 to 17 years of age on a mcg/m 2 basis).
There were no deaths following the administration of an inhalation dose of 68 mg/kg in rats (approximately 380 times the maximum recommended daily inhalation dose in adults and approximately 450 times the maximum recommended daily inhalation dose in children 6 to 17 years of age on a mcg/m 2 basis).
The minimal oral lethal dose was 200 mg/kg in mice (approximately 560 times the maximum recommended daily inhalation dose in adults and approximately 670 times the maximum recommended daily inhalation dose in children 6 to 17 years of age on a mcg/m 2 basis) and less than 100 mg/kg in rats (approximately 560 times the maximum recommended daily inhalation dose in adults and approximately 670 times the maximum recommended daily inhalation dose in children 6 to 17 years of age based on a mcg/m 2 basis).
Post-marketing experience showed that acute overdose of inhaled budesonide commonly remained asymptomatic.
The use of excessive doses (up to 6400 mcg daily) for prolonged periods showed systemic corticosteroid effects such as hypercorticism.
DESCRIPTION
11 Budesonide, the active component of PULMICORT FLEXHALER, 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 C 25 H 34 O 6 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 10 3 .
PULMICORT FLEXHALER is an inhalation-driven multi-dose dry powder inhaler containing a formulation of 1 mg per actuation of micronized budesonide and micronized lactose monohydrate which contains trace levels of milk proteins [see Contraindications (4) and Post-marketing Experience (6.2) ].
Each actuation of PULMICORT FLEXHALER 180 mcg delivers 160 mcg budesonide from the mouthpiece and each actuation of PULMICORT FLEXHALER 90 mcg delivers 80 mcg budesonide from the mouthpiece (based on in vitro testing at 60 L/min for 2 sec).
Each PULMICORT FLEXHALER 180 mcg contains 120 actuations and each PULMICORT FLEXHALER 90 mcg contains 60 actuations.
In vitro testing has shown that the dose delivery for PULMICORT FLEXHALER is dependent on airflow through the device, as evidenced by a decrease in the fine particle dose at a flow rate of 30 L/min to a value that is approximately 40-50% of that produced at 60 L/min.
At a flow rate of 40 L/min, the fine particle dose is approximately 70% of that produced at 60 L/min.
Patient factors such as inspiratory flow rates will also affect the dose delivered to the lungs of patients in actual use [see Patient Information and Instructions for Use (17.11) ].
In asthmatic children age 6 to 17 (N=516, FEV 1 2.29 [0.97– 4.28]) peak inspiratory flow (PIF) through PULMICORT FLEXHALER was 72.5 [19.1 – 103.6] L/min).
Inspiratory flows were not measured in the adult pivotal study.
Patients should be carefully instructed on the use of this drug product to assure optimal dose delivery.
structural formula
CLINICAL STUDIES
14 14.1 Asthma The safety and efficacy of PULMICORT FLEXHALER were evaluated in two 12-week, double-blind, randomized, parallel-group, placebo-controlled clinical studies conducted at sites in the United States and Asia involving 1137 patients aged 6 to 80 years with mild to moderate asthma.
Study 1 evaluated PULMICORT FLEXHALER 180 mcg, PULMICORT TURBUHALER 200 mcg, and placebo, each administered as 1 inhalation once daily or 2 inhalations twice daily in patients 18 years of age and older with mild to moderate asthma previously treated with inhaled corticosteroids.
The delivered dose of PULMICORT FLEXHALER 180 mcg and PULMICORT TURBUHALER 200 mcg are the same; each delivers 160 mcg from the mouthpiece.
Study 2 evaluated PULMICORT FLEXHALER 90 mcg, 2 inhalations once daily or 4 inhalations twice daily, PULMICORT TURBUHALER 200 mcg, 1 inhalation once daily or 2 inhalations twice daily, and placebo in pediatric patients aged 6 to 17 years with mild to moderate asthma.
Both of the studies had a 2-week placebo treatment run-in period followed by a 12-week randomized treatment period.
The primary endpoint was the difference between baseline and the mean of the treatment-period FEV 1 (adults) or FEV 1 % predicted (children).
Patients ≥ 18 years of age and older (Study 1) This study enrolled 621 patients aged ≥18 to 80 years with mild-to-moderate asthma (mean baseline % predicted FEV 1 64.3%) whose symptoms were previously controlled on inhaled corticosteroids.
Mean change from baseline in FEV 1 in the PULMICORT FLEXHALER 180 mcg, 2 inhalations twice-daily group was 0.28 liters, as compared to 0.10 liters in the placebo group (p<0.001).
Secondary endpoints of morning and evening peak expiratory flow rate, daytime asthma symptom severity, nighttime asthma symptom severity, daily rescue medication use, and the percentage of patients who met predefined asthma related withdrawal criteria showed differences from baseline favoring PULMICORT FLEXHALER over placebo (p<0.001).
12-Week Trial in Adult Patients with Mild to Moderate Asthma (Study 1) Mean Change from Baseline in FEV 1 (L) Footnote: PULMICORT TURBUHALER; a different PULMICORT DPI.
Statistical model is analysis of covariance with treatment and region (US/Asia) as factors and the baseline value as the covariate.
Patients 6 to 17 years of age (Study 2) This study enrolled 516 patients aged 6 to 17 years with mild asthma (mean baseline % predicted FEV 1 84.9%).
The study population included patients previously treated with inhaled corticosteroids for no more than 30 days before the study began (4%) and patients who were naïve to inhaled corticosteroids (96%).
Mean change from baseline in % predicted FEV 1 during the 12-week treatment period in the PULMICORT FLEXHALER 90 mcg, 4 inhalations twice daily treatment group was 5.6 compared with 0.2 in the placebo group (p<0.001).
Secondary endpoints of morning and evening PEF showed differences from baseline favoring PULMICORT FLEXHALER over placebo (p<0.001).
12-Week Trial in Pediatric Patients With Mild Asthma (Study 2) Mean Change from Baseline in Percent Predicted FEV 1 Footnote: PULMICORT TURBUHALER; a different PULMICORT DPI.
Statistical model is analysis of covariance with treatment and region (US/Asia) as factors and the baseline value as the covariate.
figure 1 figure 2
HOW SUPPLIED
16 /STORAGE AND HANDLING PULMICORT FLEXHALER is available as a dry powder for inhalation containing budesonide in the following strength: 90 mcg.
Each dosage strength contains 60 actuations per device.
90 mcg/dose, 60 dose (NDC 21695-291-01) with a target fill weight of 165 mg (range 140-190).
PULMICORT FLEXHALER consists of a number of assembled plastic details, the main parts being the dosing mechanism, the storage unit for drug substance, and the mouthpiece.
The inhaler is protected by a white outer tubular cover screwed onto the inhaler.
The body of the inhaler is white and the turning grip is brown.
The PULMICORT FLEXHALER inhaler cannot be refilled and should be discarded when empty.
The number in the middle of the dose indicator window shows how many doses are left in the inhaler.
The inhaler is empty when the number zero (“0”) on the red background reaches the middle of the window.
If the unit is used beyond the point at which the zero reaches the middle of the window, the correct amount of medication may not be obtained and the unit should be discarded.
Store in a dry place at controlled room temperature 20-25°C (68-77°F) [see USP] with the cover tightly in place.
Keep out of the reach of children.
GERIATRIC USE
8.5 Geriatric Use Of the total number of patients in controlled clinical studies receiving inhaled budesonide, 153 (n=11 treated with PULMICORT FLEXHALER ) were 65 years of age or older and one was age 75 years or older.
No overall differences in safety were observed between these patients and younger patients.
Clinical studies did not include sufficient numbers of patients aged 65 years and over to determine differences in efficacy between elderly and younger patients.
Other reported clinical or medical surveillance experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
DOSAGE FORMS AND STRENGTHS
3 PULMICORT FLEXHALER is available as a dry powder for inhalation containing budesonide in the following 2 strengths: 90 mcg and 180 mcg.
Each inhaler contains 60 or 120 actuations.
FLEXHALER device containing budesonide (90 mcg or 180 mcg) as an inhalation powder.
(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 this is unknown.
The activity of PULMICORT FLEXHALER 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 known.
Inflammation is an important component in the pathogenesis of asthma.
Corticosteroids 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 of inhaled budesonide.
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).
INDICATIONS AND USAGE
1 PULMICORT FLEXHALER is a corticosteroid indicated for: • Maintenance treatment of asthma as prophylactic therapy in adult and pediatric patients six years of age or older.
(1.1) Important Limitations: • Not indicated for the relief of acute bronchospasm.
(1.1) 1.1 Treatment of Asthma PULMICORT FLEXHALER is indicated for the maintenance treatment of asthma as prophylactic therapy in patients six years of age or older.
Important Limitations of Use: PULMICORT FLEXHALER is NOT indicated for the relief of acute bronchospasm.
PEDIATRIC USE
8.4 Pediatric Use In a 12-week pivotal study, 204 patients 6 to 17 years of age were treated with PULMICORT FLEXHALER twice daily [see Clinical Studies (14.1) ].
Efficacy results in this age group were similar to those observed in patients 18 years and older.
There were no obvious differences in the type or frequency of adverse events reported in this age group compared with patients 18 years of age and older.
The safety and effectiveness of PULMICORT FLEXHALER in asthma patients below 6 years of age have not been established.
Controlled clinical studies have shown that orally inhaled corticosteroids, including budesonide, may cause a reduction in growth velocity in pediatric patients.
This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA-axis function.
The long-term effects of this reduction in growth velocity associated with 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 5-12 years of age, those treated with inhaled budesonide via a different PULMICORT 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 a different PULMICORT 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 administration of inhaled budesonide via a different PULMICORT dry-powder inhaler in doses up to 800 mcg/day (mean daily dose 445 mcg/day) or via a pressurized metered-dose inhaler in doses up to 1200 mcg/day (mean daily dose 620 mcg/day) to 216 pediatric patients (age 3 to 11 years) for 2 to 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 inhaled budesonide on growth is not fully known.
The growth of pediatric patients receiving orally inhaled corticosteroids, including PULMICORT FLEXHALER, should be monitored (eg, via stadiometry).
If a child or adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect should be considered.
The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained.
To minimize the systemic effects of inhaled corticosteroids, including PULMICORT FLEXHALER, each patient should be titrated to the lowest dose that effectively controls his/her asthma [see Dosage and Administration (2) ].
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 1995-1997 (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 FLEXHALER should be used during pregnancy only if clearly needed.
As with other glucocorticoids, budesonide produced fetal loss, decreased pup weight, and skeletal abnormalities at a subcutaneous dose in rabbits that was approximately 0.3 times the maximum recommended daily inhalation dose in adults on a mcg/m 2 basis and at a subcutaneous dose in rats that was approximately 3 times the maximum recommended daily inhalation dose in adults on a mcg/m 2 basis.
No teratogenic or embryocidal effects were observed in rats when budesonide was administered by inhalation at doses up to approximately equivalent to the maximum recommended daily inhalation dose in adults on a mcg/m 2 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 available in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother [see Clinical Pharmacology, Pharmacokinetics, Special Populations, Nursing Mothers (12.3) ].
No studies have been conducted in breastfeeding women specifically with PULMICORT FLEXHALER; 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.
PULMICORT FLEXHALER 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.
Dosing considerations include prescription or titration to the lowest clinically effective dose and use of PULMICORT FLEXHALER immediately after breastfeeding to maximize the time interval between dosing and breastfeeding to minimize infant exposure.
However, in general, PULMICORT FLEXHALER use should not delay or interfere with infant feeding.
BOXED WARNING
Important Note: This medicine is to only be inhaled through the mouth (by oral inhalation only).
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS • Localized infections: Candida albicans infection 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 asthma or acute episodes: PULMICORT FLEXHALER should not be used for relief of acute symptoms.
Patients require immediate re-evaluation during rapidly deteriorating asthma.
(5.2) • Hypersensitivity reactions: Anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of PULMICORT FLEXHALER.
Discontinue PULMICORT FLEXHALER 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 PULMICORT FLEXHALER.
(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 PULMICORT FLEXHALER slowly.
(5.6) • Reduction in bone mineral density with long term administration.
Monitor patients with major risk factors for decreased bone mineral content.
(5.8) • Effects on growth: Monitor growth of pediatric patients.
(5.9) • Glaucoma and cataracts: Close monitoring is warranted.
(5.10) • Paradoxical bronchospasm: Discontinue PULMICORT FLEXHALER and institute alternative therapy if paradoxical bronchospasm occurs.
(5.11) • Eosinophilic conditions and Churg-Strauss: Be alert to eosinophilic conditions.
(5.12) 5.1 Local Effects In clinical studies, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in patients treated with PULMICORT FLEXHALER.
When such an infection develops, it should be treated with appropriate local or systemic (i.e.
oral antifungal) therapy while treatment with PULMICORT FLEXHALER continues, but at times, therapy with PULMICORT FLEXHALER may need to be interrupted.
Patients should rinse the mouth after inhalation of PULMICORT FLEXHALER.
5.2 Deterioration of Asthma or Acute Episodes PULMICORT FLEXHALER is not a bronchodilator and is not indicated for the rapid relief of 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 PULMICORT FLEXHALER.
During such episodes, patients may require therapy with oral corticosteroids.
An inhaled short acting beta 2 -agonist, not PULMICORT FLEXHALER, should be used to relieve acute symptoms such as shortness of breath.
When prescribing PULMICORT FLEXHALER, the physician must also provide the patient with an inhaled, short-acting beta 2 -agonist (e.g.
albuterol) for treatment of acute symptoms, despite regular twice-daily (morning and evening) use of PULMICORT FLEXHALER.
5.3 Hypersensitivity Reactions Including Anaphylaxis Hypersensitivity reactions including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of PULMICORT FLEXHALER.
Discontinue PULMICORT FLEXHALER if such reactions occur [see Contraindications (4) and Adverse Reactions (6) ].
PULMICORT FLEXHALER contains small amounts of lactose, which contains trace levels of milk proteins.
It is possible that cough, wheezing, or bronchospasm may occur in patients who have a severe milk protein allergy [see Contraindications (4) and Adverse Reactions, Post-marketing Experience (6.2) ].
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 affects the risk of developing a disseminated infection is not known.
The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known.
If exposed to 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 immune responsiveness to varicella vaccine was evaluated in pediatric patients with asthma ages 12 months to 8 years with budesonide inhalation suspension.
An open-label, nonrandomized clinical study examined the immune responsiveness to 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 non-corticosteroid asthma therapy (n=92) (i.e., beta 2 -agonists, leukotriene receptor antagonists, cromones).
The percentage of patients developing a seroprotective antibody titer of ≥5.0 (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 PULMICORT FLEXHALER 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) 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 FLEXHALER 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.
Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to PULMICORT FLEXHALER.
Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with PULMICORT FLEXHALER.
Lung function (mean forced expiratory volume in 1 second [FEV 1 ] or morning peak expiratory flow [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 PULMICORT FLEXHALER may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy, (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).
Some 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 PULMICORT FLEXHALER will often help control 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 beneficial effects of PULMICORT FLEXHALER 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 FLEXHALER.
Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with PULMICORT FLEXHALER 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 (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 PULMICORT FLEXHALER should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms.
5.7 Interactions with Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the co-administration of PULMICORT FLEXHALER 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 [ee Drug Interactions (7.1), Clinical Pharmacology (12.3) ].
5.8 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 consequences such as fracture is unknown.
Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, post menopausal status, tobacco use, advance age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g, anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care.
5.9 Effect 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 PULMICORT FLEXHALER routinely (e.g., via stadiometry).
To minimize the systemic effects of orally inhaled corticosteroids, including PULMICORT FLEXHALER, titrate each patient’s dose to the lowest dosage that effectively controls his/her symptoms [see Dosage and Administration (2.1), Use in Specific Populations (8.4) ].
5.10 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.
5.11 Paradoxical Bronchospasm and Upper Airway Symptoms As with other inhaled asthma medications, PULMICORT FLEXHALER can produce paradoxical bronchospasm, which may be life threatening.
If paradoxical bronchospasm occurs following dosing with PULMICORT FLEXHALER, it should be treated immediately with an inhaled, short-acting beta 2 – bronchodilator.
PULMICORT FLEXHALER should be discontinued immediately, and alternative therapy should be instituted.
5.12 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 corticosteroid 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.
Physicians should be alert to eosinophilia, vasculitic 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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Patients being treated with PULMICORT FLEXHALER 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.
For proper use of PULMICORT FLEXHALER and to attain maximum improvement, the patient should read and follow the accompanying FDA Approved Patient Labeling.
17.1 Oral Candidiasis Patients should be advised that 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 therapy with PULMICORT FLEXHALER, but at times therapy with PULMICORT FLEXHALER may need to be temporarily interrupted under close medical supervision.
Rinsing the mouth after inhalation is advised.
[see Warnings and Precautions (5.1) ] 17.2 Not for Acute Symptoms PULMICORT FLEXHALER 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 beta 2 -agonist such as albuterol (The physician should provide that patient with such medication and instruct the patient in how it should be used.) Patients should be instructed to notify their physician immediately if they experience any of the following: Decreasing effectiveness of inhaled, short-acting beta 2 -agonists Need for more inhalations than usual of inhaled, short-acting beta 2 -agonists Significant decrease in lung function as outlined by the physician Patients should not stop therapy with PULMICORT FLEXHALER without physician/provider guidance since symptoms may recur after discontinuation.
[see Warnings and Precautions (5.1) ] 17.3 Hypersensitivity including Anaphylaxis Hypersensitivity reactions including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of PULMICORT FLEXHALER.
Discontinue PULMICORT FLEXHALER if such reactions occur [see Contraindications (4), Warnings and Precautions (5.3), and Adverse Reactions (6) ].
PULMICORT FLEXHALER contains small amounts of lactose, which contains trace levels of milk proteins.
It is possible that cough, wheezing, or bronchospasm may occur in patients who have a severe milk protein allergy [see Contraindications (4) ].
17.4 Immunosuppression Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay.
Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex [see Warnings and Precautions (5.4) ].
17.5 Hypercorticism and Adrenal Suppression Patients should be advised that PULMICORT FLEXHALER 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 PULMICORT FLEXHALER [see Warnings and Precautions (5.5, 5.6) ].
17.6 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 (5.8) ].
17.7 Reduced Growth Velocity Patients should be informed that orally inhaled corticosteroids, including budesonide inhalation powder, may cause a reduction in growth velocity when administered to pediatric patients.
Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route [see Warnings and Precautions (5.9) ].
17.8 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 (5.10) ].
17.9 Use Daily Patients should be advised to use PULMICORT FLEXHALER at regular intervals, since its effectiveness depends on regular use.
Maximum benefit may not be achieved for 1 to 2 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 physician.
17.10 How to Use Pulmicort Flexhaler Patients should be carefully instructed on the use of this drug product to assure optimal dose delivery.
The patient may not sense the presence of any medication entering their lungs when inhaling from PULMICORT FLEXHALER.
This lack of sensation does not mean that they did not get the medication.
They should not repeat their inhalation even if they did not feel the medication when inhaling [see Patient Information ].
17.11 FDA–Approved Patient Labeling
DOSAGE AND ADMINISTRATION
2 PULMICORT FLEXHALER should be administered twice daily by the orally inhaled route only.
After inhalation, the patient should rinse the mouth with water without swallowing [see Patient Counseling Information (17.1) ].
Patients should be instructed to prime PULMICORT FLEXHALER prior to its initial use, and instructed to inhale deeply and forcefully each time the device is used.
The safety and efficacy of PULMICORT FLEXHALER when administered in excess of recommended doses have not been established.
After asthma stability has been achieved, it is desirable to titrate to the lowest effective dosage to reduce the possibility of side effects.
For patients who do not respond adequately to the starting dose after 1-2 weeks of therapy with PULMICORT FLEXHALER, increasing the dose may provide additional asthma control.
For oral inhalation only.
Patients 18 Years of Age and Older: For patients 18 years of age and older, the recommended starting dosage is 360 mcg twice daily.
In some adult patients, a starting dose of 180 mcg twice daily may be adequate.
The maximum dosage should not exceed 720 mcg twice daily.
(2.1) Patients 6 to 17 Years of Age: The recommended starting dosage is 180 mcg twice daily.
In some pediatric patients, a starting dose of 360 mcg twice daily may be appropriate.
The maximum dosage should not exceed 360 mcg twice daily.
(2.1) 2.1 Asthma If asthma symptoms arise in the period between doses, an inhaled, short-acting beta 2 -agonist should be taken for immediate relief.
Patients 18 Years of Age and Older: For patients 18 years of age and older, the recommended starting dosage is 360 mcg twice daily.
In some adult patients, a starting dose of 180 mcg twice daily may be adequate.
The maximum dosage should not exceed 720 mcg twice daily.
Patients 6 to 17 Years of Age: The recommended starting dosage is 180 mcg twice daily.
In some pediatric patients, a starting dose of 360 mcg twice daily may be appropriate.
The maximum dosage should not exceed 360 mcg twice daily.
For all patients, it is desirable to titrate to the lowest effective dose after adequate asthma stability is achieved.
Improvement in asthma control following inhaled administration of budesonide can occur within 24 hours of initiation of treatment, although maximum benefit may not be achieved for 1 to 2 weeks, or longer.
Individual patients will experience a variable onset and degree of symptom relief.
If a previously effective dosage regimen of PULMICORT FLEXHALER fails to provide adequate control of asthma, the therapeutic regimen should be re-evaluated and additional therapeutic options (e.g.
replacing the lower strength of PULMICORT FLEXHALER with the higher strength or initiating oral corticosteroids) should be considered.