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.
Budesonide Inhalation Suspension Dosage and Administration
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 twice daily in divided doses | 0.5 mg total daily dose |
| Inhaled Corticosteroids | 0.5 mg total daily dose administered twice daily in divided doses | 1 mg total daily dose |
| Oral Corticosteroids | 1 mg total daily dose administered as 0.5 mg twice daily | 1 mg total daily dose |
Dosing Recommendations
Dosing recommendations based on previous therapy are as follows:
- Bronchodilators alone: 0.25 mg twice daily
- Inhaled corticosteroids: 0.25 mg twice daily up to 0.5 mg twice daily
- Oral corticosteroids: 0.5 mg twice daily
In all patients, it is desirable to downward-titrate to the lowest effective dose once asthma stability is achieved.
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.
Dosage Forms and Strengths
Budesonide Inhalation Suspension is available in two strengths, each containing 2 mL: 0.25 mg/2 mL and 0.5 mg/2 mL. Budesonide Inhalation Suspension is supplied in sealed aluminum foil envelopes containing one plastic strip of five single-dose vials. There are 30 vials in a carton. Each single-dose vial contains 2 mL of sterile liquid suspension.
Contraindications
The use of Budesonide Inhalation Suspension is contraindicated in the following conditions:
- Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.
- Hypersensitivity to budesonide or any of the ingredients of Budesonide Inhalation Suspension [see Warnings and Precautions (5.3), Description (11) and Adverse Reactions, Post-marketing Experience (6.2)].
Warnings and Precautions
Local Effects
In clinical trials with Budesonide Inhalation Suspension, 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 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.
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.
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)].
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 ≥5.0 (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.
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.
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.
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.
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)].
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.
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.
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.
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)].
Adverse Reactions
Systemic and inhaled corticosteroid use may result in the following:
- Candida albicans infection [see Warnings and Precautions (5.1)]
- Hypersensitivity reactions including anaphylaxis [see Warnings and Precautions (5.3)]
- Immunosuppression [see Warnings and Precautions (5.4)]
- Hypercorticism and adrenal suppression [see Warnings and Precautions (5.6)]
- Reduction in bone mineral density [see Warnings and Precautions (5.7)]
- Growth effects in pediatric patients [see Warnings and Precautions (5.8) and Use in Specific Populations, Pediatric Use (8.4)]
- Glaucoma, increased intraocular pressure and cataracts [see Warnings and Precautions (5.9)]
- Eosinophilic conditions and Churg-Strauss syndrome [see Warnings and Precautions (5.11)]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The incidence of common adverse reactions is based on three double-blind, placebo-controlled, randomized U.S. 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 Budesonide Inhalation Suspension (0.25 to 1 mg total daily dose for 12 weeks) or vehicle placebo. The incidence and nature of adverse events reported for Budesonide Inhalation Suspension was comparable to that reported for placebo. The following table shows the incidence of adverse events in U.S. 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 and 78.4% were Caucasian, 13.8% African American, 5.5% Hispanic and 2.3% Other.
| Budesonide | ||||
| Vehicle Placebo (n = 227) % | Total Daily Dose | |||
| 0.25 mg (n=178) % | 0.5 mg (n = 223) % | 1 mg (n = 317) % | ||
| Adverse Events | ||||
| 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 |
The information below includes all adverse reactions by system organ class with an incidence of 1 to < 3%, in at least one Budesonide Inhalation Suspension treatment group where the incidence was higher with Budesonide Inhalation Suspension than with placebo, regardless of relationship to treatment.
Blood and lymphatic system disorders: cervical lymphadenopathy
Ear and labyrinth disorders: earache
General disorders and administration site conditions: fatigue, flu-like disorder
Immune system disorders: allergic reaction
Infections and infestations: eye infection, herpes simplex, external ear infection, infection
Injury, poisoning and procedural complication: fracture
Metabolism and nutrition disorders: anorexia
Musculoskeletal and connective tissue disorders: myalgia
Nervous system disorders: hyperkinesia
Psychiatric disorders: emotional lability
Respiratory, thoracic, and mediastinal disorders: chest pain, dysphonia, stridor
Skin and subcutaneous tissue disorders: contact dermatitis, eczema, pustular rash, pruritus, purpura
The incidence of reported adverse events was similar between the 447 Budesonide Inhalation Suspension-treated (mean total daily dose 0.5 to 1 mg) and 223 conventional therapy-treated pediatric asthma patients followed for one year in three open-label studies.
Post-marketing Experience
The following adverse reactions have been reported during post-approval use of Budesonide Inhalation Suspension. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Some of these adverse reactions may also have been observed in clinical studies with Budesonide Inhalation Suspension.
Endocrine disorders: symptoms of hypocorticism and hypercorticism [see Warnings and Precautions (5.5)]
Eye disorders: cataracts, glaucoma, increased intraocular pressure [see Warnings and Precautions (5.9)]
General disorders and administration site conditions: fever, pain
Immune system disorders: immediate and delayed hypersensitivity reactions including, anaphylaxis, angioedema, bronchospasm, rash, contact dermatitis, and urticaria [see Contraindications (4) and Warnings and Precautions (5.10)]
Infection and Infestation: sinusitis, pharyngitis, bronchitis
Musculoskeletal and connective tissue disorders: avascular necrosis of the femoral head, osteoporosis, growth suppression
Nervous system disorders: headache
Psychiatric disorders: psychiatric symptoms including psychosis, depression, aggressive reactions, irritability, nervousness, restlessness, and anxiety
Respiratory, thoracic, and mediastinal disorders: cough, dysphonia and throat irritation
Skin and subcutaneous tissue disorders: skin bruising, facial skin irritation
Cases of growth suppression have been reported for inhaled corticosteroids including post-marketing reports for Budesonide Inhalation Suspension [see Warnings and Precautions (5.8) and Use In Specific Populations, Pediatric Use (8.4)].
Drug Interactions
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 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 (5.12) and Clinical Pharmacology, Pharmacokinetics (12.3)].
USE IN SPECIFIC POPULATIONS
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 (ie, 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, 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.
Non-teratogenic Effects:
Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully observed.
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.
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)].
It has been reported a study in pediatric patients 6 to 12 months of age with mild to moderate asthma or recurrent/persistent wheezing. All patients were randomized to receive either Budesonide Inhalation Suspension or placebo. 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 1.0) 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 5-12 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) and Warnings and Precautions (5.8)].
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.
Hepatic Impairment
Formal pharmacokinetic studies using Budesonide Inhalation Suspension inhalation suspension have not been conducted in patients with hepatic impairment. However, since budesonide is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of budesonide in plasma. Therefore, patients with hepatic disease should be closely monitored.
Overdosage
The potential for acute toxic effects following overdose of budesonide 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 or and children 12 months to 8 years of age on a mg/m2 basis).
Budesonide Inhalation Suspension Description
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) and it has the following structural formula:
Budesonide Inhalation Suspension 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.
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, tri-sodium citrate dihydrate and water for injection.
Two dose strengths are available in single-dose vials: 0.25 mg and 0.5 mg per 2 mL vial. 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)].
Budesonide Inhalation Suspension - Clinical Pharmacology
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 (85-95%) and the low potency of metabolites (see below).
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 mcg budesonide administered via a pressurized metered dose inhaler with a tube spacer to 1400 mcg of oral budesonide and placebo. The study demonstrated the efficacy of inhaled budesonide but not orally administered budesonide, even though systemic budesonide exposure was comparable for both treatments, indicating that the inhaled treatment is working locally in the lung. Thus, the therapeutic effect of conventional doses of orally inhaled budesonide are largely explained by its direct action on the respiratory tract.
Improvement in the control of asthma symptoms following inhalation of Budesonide Inhalation Suspension can occur within 2-8 days of beginning treatment, although maximum benefit may not be achieved for 4-6 weeks.
Budesonide administered via a dry powder inhaler 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 as 1600 mcg daily (800 mcg twice daily) via a dry powder inhaler for 2 weeks reduced the acute (early-phase reaction) and delayed (late-phase reaction) decrease in FEV1 following inhaled allergen challenge.
HPA Axis Effects
The effects of Budesonide Inhalation Suspension 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 Budesonide Inhalation Suspension treatment at recommended doses. In the subgroup of children age 6 months to 2 years (n=21) treated with a total daily dose of Budesonide Inhalation Suspension up to 1 mg or placebo, 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 sign
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