Drug Criteria & Outcomes
Review: Budesonide inhalation suspension
By Rafe Holmes, PharmD Candidate
College of Pharmacy
University of Texas
Austin, TX
Barry Browne, PharmD
Coordinator of Drug Information
Scott and White Hospital and Health Plan
Temple, TX
Introduction:
Inhaled corticosteroids are commonly used as anti-inflammatory agents to help prevent recurrent asthma exacerbations. The 1997 National Heart, Lung and Blood Institute (NHLBI) guidelines recommend their use in many patients with mild persistent, moderate persistent, and severe persistent asthma. Corticosteroids are generally considered to be the most potent long-term "controller" asthma medications available.
Inhaled corticosteroids needed
By reducing inflammation, current research indicates that reduction/prevention of airway tissue remodeling may be possible. Airway remodeling has been associated with the chronic symptoms that are commonly linked to this disease.1 The lack of a nebulizable corticosteroid has complicated the treatment of persistent asthma in young children and infants who are unable to properly manipulate metered-dose-inhalers (MDIs).
Previous corticosteroid treatment for children included inhaled corticosteroids via MDI delivery, with the MDIs fitted with a spacer/holding chamber to improve drug delivery. If control was not achieved through this method, then systemic corticosteroids were considered.2 Although nebulized cromolyn sodium has been shown to be an effective alternative for infants and young children with persistent asthma, in many cases, this agent lacks the efficacy provided by corticosteroids.1
The Food and Drug Administration (FDA) has recently approved budesonide inhalation suspension (Pulmicort Respules) by AstraZeneca Pharmaceuticals. The budesonide active ingredient is identical to the Pulmicort Turbuhaler, save for the delivery system. Thus, budesonide is now available as the only corticosteroid for nebulization, for use in air-driven jet nebulizers. When administered on a regular basis, Pulmicort Respules have been shown to improve lung function, decrease asthma symptoms, and reduce the use of as-needed inhaled beta-agonists.2
Indications:
Budesonide inhalation suspension (Pulmicort Respules), approved by the FDA in August 2000, is the first and only nebulizable corticosteroid. The agent is indicated for the maintenance treatment of asthma and as prophylactic therapy in children ages 12 months to 8 years.
Clinical pharmacology:
Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. Corticosteroids have been shown to exhibit a wide range of inhibitory activities against multiple cell types (mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic and non-allergic mediated inflammation. The anti-inflammatory effects of corticosteroids are thought to provide efficacy in the treatment of asthma. Studies have shown a favorable ratio between the topical anti-inflammatory activities and systemic corticosteroid effects in asthmatic patients for budesonide at a wide range of doses. This effect is likely due to the high local anti-inflammatory effects, 85-95% first pass metabolism of orally absorbed drug, and low potency of metabolites.2
Pharmacokinetics:
Absorption: In asthmatic children 4 to 6 years of age, the total absolute bioavailability (lung and oral) of Pulmicort Respules following nebulization via jet nebulizer was approximately 6% of the labeled dose.
Distribution: In asthmatic children 4 to 6 years of age, the volume of distribution at steady- state was 3 L/kg, approximately the same as that for healthy adults. Budesonide is 85-90% bound to plasma proteins, which is constant over concentration ranges from 1-100nmol/L. Budesonide shows little or no binding to corticosteroid-binding globulin.
Metabolism: In vitro studies with human liver homogenates have shown that budesonide is rapidly and extensively metabolized by the Cytochrome P450 3A isoenzyme to two major metabolites. The corticosteroid activity of each metabolite is less than 1% of that for the parent drug. Reduced liver function may affect the metabolism of budesonide.
Excretion: Budesonide is excreted in the urine and feces as the inactive metabolites.2
Clinical trials:
Three randomized, double-blind, placebo-controlled parallel group U.S. clinical trials of 12 weeks duration each were conducted in 1,018 pediatric patients ages 6 months to 8 years. Patients had persistent asthma with varying severity and disease duration. Doses of 0.25 mg, 0.5 mg, and 1 mg administered either once or twice daily by face mask or mouthpiece were compared to placebo to determine the appropriate dosing over a range of asthma severity. Among the primary endpoints were daytime and nighttime symptoms. Compared to placebo, treatment with Pulmicort Respules significantly decreased both daytime and nighttime symptoms scores (P < 0.05) at doses of 0.25 mg once daily (in one study), 0.25 mg twice daily, and at 0.5 mg twice daily. The agent significantly decreased either daytime or nighttime symptoms scores, but not both, at doses of 0.5 mg once daily and 1 mg once daily (P < 0.05). Pulmicort Respules significantly reduced the need for bronchodilator therapy in all of the study doses (P < 0.014-P < 0.038). In one of the studies, significant improvements were seen in FEV1 at doses of 0.5 mg once daily (P < 0.044) and 1 mg once daily (P < 0.033), and at doses of 0.5 mg twice daily (P < 0.043) in another study. Morning PEF was significantly improved in patients receiving Pulmicort Respules 0.25 mg once daily (P < 0.03; one study), 0.25 mg twice daily and 0.5 mg twice daily (P < 0.03).3-5
Dosage:
The recommended starting dose of Pulmicort Respules, when previous therapy was a bronchodilator alone, is 0.5 mg total daily dose, administered once or twice daily. The highest recommended dose for these patients is 0.5 mg/day. When previous therapy consisted of inhaled corticosteroids, the recommended starting dose of Pulmicort Respules is 0.5 mg total daily dose, given once or twice daily. The highest recommended dose in this case is 1 mg/day. For those whose previous therapy consisted of oral corticosteroids, the recommended starting dose of Pulmicort Respules is 1 mg total daily dose, administered once or twice daily. The highest recommended dose in this case is 1 mg/day.
Administration:
As noted above, the agent is administered (five to 10 minutes per treatment) via a jet nebulizer (not for use in ultrasonic nebulizer). The Pari-LC-Jet Plus nebulizer and Pari Master compressor were effective in clinical trials when used with a facemask or mouthpiece. Initial improvement is typically seen within two to eight days, although the maximum benefit may take as long as four to six weeks. Pulmicort should be titrated to the lowest effective dose to avoid adverse effects. Gradual reduction of systemic corticosteroids may begin after one week of Pulmicort Respules therapy.
Adverse reactions:
The incidence and type of adverse events for Pulmicort Respules reported in clinical trials were comparable to those for placebo. At total daily doses of 0.25 mg, 0.5 mg, 1 mg, and placebo, adverse events were: respiratory infections 34-38%, rhinitis 7-12%, cough 5-9%, otitis media 9-12%, viral infection 3-5%, gastroenteritis 4-5%, ear infection 2-5%, and epistaxis 1-4%. Oral and oropharyngeal fungal infections occurred in 2-4% of the patients.
Contraindications:
Pulmicort Respules are contraindicated as primary treatment for status asthmaticus and for other acute episodes of asthma. The agent is also contraindicated if the patient has a history of hypersensitivity to budesonide or other components of the product.
Warnings:
Caution is advised when switching patients from systemic corticosteroid therapy to inhaled corticosteroids; hypothalamic-pituitary-adrenal (HPA) axis suppression should be monitored. Exposure to corticosteroid therapy may increase patients’ susceptibility to infections. Avoid eye exposure when using a facemask, as localized exposure to corticosteroids has been associated with cataract formation. Also, rinsing2 the face after treatments by facemask helps to prevent irritation which may be caused by the drug, solvents and, or propellants. The patient should rinse the mouth after each budesonide treatment to minimize the risk for fungal infection. Budesonide is a category C prescription. Potential risks and benefits to mother and fetus should be considered before use during pregnancy.
Drug interactions:
Coadministration with ketoconazole may cause increased budesonide plasma levels. As budesonide is a cytochrome P450 3A isoenzyme substrate, the agent has the potential for other drug interactions, especially with drugs which induce and, or inhibit this isoenzyme. However, further data is needed to determine if any drug interactions will be clinically significant, in that the agent is administered by nebulization and systemic absorption is somewhat decreased. The effect of mixing Pulmicort Respules with other medications has not been adequately studied. Currently, Pulmicort Respules should be administered separately from nebulized drugs. Limited data suggest that no increased frequency of adverse events or change in efficacy when budesonide is mixed with either ipratropium (Atrovent) by nebulization or with nebulized albuterol.6
Availability:
Pulmicort Respules are available in two strengths: 0.25 mg/2 mL and 0.5 mg/2 mL.
Packaging:
The product comes six aluminum foil envelopes per carton, five single dose Pulmicort Respules per envelope, each containing 2 mL of budesonide suspension (30 total doses).
Storage:
Unused Pulmicort Respules should be kept in the foil envelope to avoid light exposure. Once the aluminum foil has been opened, remaining Pulmicort Respules should be used within two weeks of opening the foil envelope. Store at room temperature.2
Cost:
The associated wholesale price (AWP) of both strengths of Pulmicort Respules, per carton of 30 doses, is $126.6
Summary:
Based on the available clinical trials required for FDA approval, Pulmicort Respules appear to provide safe and effective treatment for children and infants with non-steroid dependent and steroid-dependent persistent asthma when administered by jet nebulization with either facemask or mouthpiece. Daily dosing is an important option to be considered.2
References:
1. Murphy S. Guidelines for the diagnosis and management of asthma. National Heart, Lung, And Blood Institute. May 1997:1-50.
2. Pulmicort Respules product information. Wayne, PA: AstraZeneca; 2000.
3. Kemp JP, Skoner DP, Szefler SJ, et al. Once-daily budesonide inhalation suspension for the treatment of persistent asthma in infants and young children. Ann Allergy Asthma Immunol 1999; 83:231-9.
4. Shapiro G, Mendelson L, Kraemer MJ, et al. Efficacy and safety of budesonide inhalation suspension in young children with inhaled steroid- dependent, persistent asthma. J Allergy Clin Immunol 1998; 102:789-96.
5. Baker JW, Mellon M, Wald J, et al. A multiple-dosing, placebo-controlled study of budesonide inhalation suspension given once or twice daily for treatment of persistent asthma in young children and infants. Pediatrics 1999; 103(2):414-21.
6. Scott and White Memorial Hospital. Outpatient Pharmacy October 2000.
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