Budesonide

Description

Budesonide, the active ingredient in budesonide inhalation suspension, is a corticosteroid with the chemical designation of (RS)-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20 dione cyclic 16,17-acetal with butyraldehyde. It exists as a mixture of two epimers, specifically the 22R and 22S forms. The empirical formula for budesonide is C25H34O6, and it has a molecular weight of 430.5 g/mol.

Budesonide appears as a white to off-white, tasteless, and odorless powder that is practically insoluble in water and 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.

The budesonide inhalation suspension is a sterile formulation intended for inhalation via a jet nebulizer. Each single-dose ampule contains 0.5 mg of micronized budesonide in a total volume of 2 mL, along with inactive ingredients including anhydrous citric acid, disodium edetate dihydrate, polysorbate 80, sodium chloride, sodium citrate anhydrous, and water for injection.

The delivery of budesonide to the lungs is influenced by patient-specific factors, the type of jet nebulizer used, and the performance of the compressor. In vitro studies using the Pari-LC-Jet Plus Nebulizer/Pari Master compressor system have shown that the mean delivered dose at the mouthpiece is approximately 17% of the nominal dose at a mean flow rate of 5.5 L/min, with a mean nebulization time of 5 minutes or less. Budesonide inhalation suspension should be administered using jet nebulizers at appropriate flow rates, utilizing either face masks or mouthpieces.

Uses and Indications

Budesonide inhalation suspension is indicated for the maintenance treatment of asthma and as prophylactic therapy in pediatric patients aged 12 months to 8 years.

This drug is not indicated for the relief of acute bronchospasm. There are no teratogenic or nonteratogenic effects associated with its use.

Dosage and Administration

The initial dosing regimen should commence with the lowest recommended dose tailored to the specific treatment modality. For bronchodilators administered alone, the starting dose is 0.5 mg once daily or 0.25 mg twice daily. In the case of inhaled corticosteroids, the recommended starting dose is 0.5 mg once daily or 0.25 mg twice daily, with the option to increase to a maximum of 0.5 mg twice daily if necessary. For oral corticosteroids, the initial dose is 0.5 mg twice daily.

In symptomatic children who do not respond adequately to non-steroidal therapy, a starting dose of 0.25 mg once daily may be considered. Should once-daily treatment fail to achieve sufficient control of symptoms, the total daily dose may be increased and/or administered as a divided dose. Once asthma stability is attained, it is advisable to titrate the dose downwards to the lowest effective level.

This medication is intended for inhalation use exclusively via compressed air-driven jet nebulizers; it is not suitable for use with ultrasonic devices and is not for injection.

Contraindications

Use of budesonide inhalation suspension is contraindicated in the following situations:

Patients requiring primary treatment for status asthmaticus or other acute episodes of asthma that necessitate intensive measures should not use this product. Additionally, individuals with a known hypersensitivity to any of the ingredients in budesonide inhalation suspension should avoid its use due to the risk of severe allergic reactions.

Warnings and Precautions

Localized infections, particularly Candida albicans infections of the mouth and throat, may occur in patients using budesonide inhalation suspension. Healthcare professionals should monitor patients periodically for signs of adverse effects on the oral cavity and advise them to rinse their mouths following inhalation to mitigate this risk.

Budesonide inhalation suspension is not indicated for the relief of acute bronchospasm. Therefore, it should not be used in the management of acute asthma episodes or the deterioration of disease.

Hypersensitivity reactions, including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm, have been reported with the use of budesonide inhalation suspension. If any of these reactions occur, the medication should be discontinued immediately.

Immunosuppression is a potential concern, particularly in patients with existing infections such as tuberculosis, fungal, bacterial, viral, or parasitic infections, as well as ocular herpes simplex. Caution is advised when prescribing budesonide inhalation suspension to these patients, as they may experience a more serious or even fatal course of chickenpox or measles.

When transferring patients from systemic corticosteroid therapy to budesonide inhalation suspension, there is a risk of impaired adrenal function. It is essential to taper patients slowly from oral steroids to minimize this risk.

Hypercorticism and adrenal suppression may occur, particularly with very high dosages or in susceptible individuals. Should these changes arise, the dosage of budesonide inhalation suspension should be reduced gradually.

Long-term administration of budesonide inhalation suspension may lead to a reduction in bone mineral density. Therefore, it is important to monitor patients who have major risk factors for decreased bone mineral content.

In pediatric patients, growth should be closely monitored during treatment with budesonide inhalation suspension to ensure that any potential effects on growth are identified and managed appropriately.

Patients should be monitored for the development of glaucoma and cataracts, as close observation is warranted in these cases.

Paradoxical bronchospasm may occur with the use of budesonide inhalation suspension. If this reaction is observed, the medication should be discontinued, and alternative therapy should be initiated.

Healthcare professionals should remain vigilant for eosinophilic conditions, including Churg-Strauss syndrome, in patients receiving budesonide inhalation suspension.

Budesonide inhalation suspension is intended for inhalation only and should not be swallowed. It is crucial to use this medication exclusively with a jet nebulizer machine connected to an air compressor; it should not be used with an ultrasonic nebulizer.

Monitoring parameters include assessing patients with major risk factors for decreased bone mineral content, tracking the growth of pediatric patients, and conducting close monitoring for glaucoma and cataracts.

In the event of hypersensitivity reactions, budesonide inhalation suspension should be discontinued, and emergency medical help should be sought. Additionally, if paradoxical bronchospasm occurs, the medication should be stopped, and the healthcare provider should be contacted for alternative treatment options.

Side Effects

high doses or prolonged use of budesonide inhalation suspension. Patients should be monitored for signs of hypercorticism and adrenal suppression, particularly if they are receiving other corticosteroids or have a history of adrenal insufficiency.

Most common adverse reactions observed in clinical trials included respiratory infections, rhinitis, coughing, otitis media, viral infections, moniliasis, gastroenteritis, vomiting, diarrhea, abdominal pain, ear infections, epistaxis, conjunctivitis, and rash. These reactions were reported with varying frequencies among participants.

Localized infections, particularly Candida albicans infections of the mouth and throat, may occur. It is recommended that patients be monitored periodically for signs of adverse effects on the oral cavity, and they should be advised to rinse their mouths following inhalation to mitigate this risk.

Hypersensitivity reactions have been reported with the use of budesonide inhalation suspension, including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm. In the event of such reactions, discontinuation of the medication is advised.

Immunosuppression is a potential concern, as the use of budesonide inhalation suspension may worsen existing infections, including tuberculosis, fungal, bacterial, viral, or parasitic infections, as well as ocular herpes simplex. Caution is warranted in patients with these pre-existing conditions, as a more serious or even fatal course of chickenpox or measles can occur in susceptible individuals.

Lastly, hypercorticism and adrenal suppression may arise with very high doses or prolonged use of budesonide inhalation suspension. Patients should be closely monitored for signs of these conditions, especially if they are concurrently receiving other corticosteroids or have a history of adrenal insufficiency.

Drug Interactions

The concomitant use of strong Cytochrome P450 3A4 inhibitors, such as ritonavir, should be approached with caution. Co-administration may lead to an increase in systemic corticosteroid effects, which could heighten the risk of adverse reactions associated with corticosteroid therapy.

It is advisable to monitor patients closely for signs of increased corticosteroid effects and consider dosage adjustments as necessary to mitigate potential risks.

Packaging & NDC

The table below lists all NDC Code configurations of Budesonide Inhalation, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness of budesonide inhalation suspension in pediatric patients aged six months to 12 months have been evaluated but not established. In children aged 12 months to 8 years, safety and effectiveness have been established. A 12-week study involving 141 pediatric patients aged 6 to 12 months with mild to moderate asthma or recurrent/persistent wheezing assessed the effects of budesonide inhalation suspension at doses of 0.5 mg and 1 mg compared to placebo.

Adrenal-axis function was evaluated using an ACTH stimulation test at the study's start and end, revealing no significant adrenal suppression in the budesonide groups compared to placebo. However, individual assessments indicated that 7 patients (6 in the budesonide groups and 1 in the placebo group) experienced a decline from normal to subnormal stimulated cortisol levels by Week 12.

Pneumonia occurred more frequently in patients receiving budesonide inhalation suspension, with two cases in the 0.5 mg group, one in the 1 mg group, and none in the placebo group. A dose-dependent effect on growth was observed; infants in the placebo arm grew an average of 3.7 cm over 12 weeks, while those in the 0.5 mg and 1 mg groups grew 3.5 cm and 3.1 cm, respectively. These findings suggest that budesonide inhalation suspension may lead to systemic effects, including growth suppression, consistent with other studies on inhaled corticosteroids.

Controlled clinical studies indicate that inhaled corticosteroids can reduce growth velocity in pediatric patients, with an average reduction of approximately one centimeter per year, influenced by dose and duration of treatment. The long-term implications of this growth reduction on final adult height remain unknown, and the potential for "catch up" growth after discontinuation of treatment has not been adequately studied.

In a separate study of asthmatic children aged 5 to 12 years, those treated with budesonide via a dry powder inhaler at 200 mcg twice daily experienced a 1.1-centimeter reduction in growth compared to those receiving placebo after one year. Routine monitoring of growth in pediatric patients receiving inhaled corticosteroids, including budesonide inhalation suspension, is recommended. To minimize systemic effects, each patient should be titrated to the lowest effective dose.

Geriatric Use

In clinical trials involving budesonide inhalation suspension, 30% of the 215 patients studied were aged 65 years or older, with 10% being 75 years of age or older. The data indicate that there were no overall differences in safety profiles between elderly patients and their younger counterparts. Furthermore, additional clinical and medical surveillance has not revealed any significant differences in responses to treatment between geriatric patients and younger individuals.

Given the lack of observed differences in safety and efficacy, no specific dosage adjustments are recommended for elderly patients. However, healthcare providers should remain vigilant in monitoring this population for any potential adverse effects, as individual responses may vary. It is essential to consider the overall health status and comorbidities of geriatric patients when prescribing budesonide inhalation suspension.

Pregnancy

There are no adequate well-controlled studies of budesonide inhalation suspension in pregnant women. However, published studies have not demonstrated an increased risk of abnormalities associated with the use of inhaled budesonide during pregnancy. A large population-based prospective cohort epidemiological study indicated no increased risk for congenital malformations from the use of inhaled budesonide in early pregnancy, with rates of congenital malformations among infants born to mothers using the medication being similar to the general population (3.8% vs. 3.5%). Additionally, the incidence of orofacial clefts in infants exposed to inhaled budesonide was comparable to expected rates in the general population (4 children vs. 3.3).

Animal reproduction studies have shown that budesonide can cause structural abnormalities, embryocidal effects, and reduced fetal weights in rats and rabbits at doses less than the maximum recommended human daily inhalation dose (MRHDID). Notably, these adverse effects were not observed in rats receiving inhaled doses approximately 2 times the MRHDID. It is important to note that experience with oral corticosteroids suggests that rodents may be more susceptible to structural abnormalities from corticosteroid exposure than humans.

The estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes, including preeclampsia, prematurity, low birth weight, and small for gestational age in the neonate. Therefore, pregnant women with asthma should be closely monitored, and medication should be adjusted as necessary to maintain optimal asthma control.

There are no well-controlled human studies investigating the effects of budesonide inhalation suspension during labor and delivery. While budesonide has not been shown to affect delivery, it has been associated with growth and developmental impacts on offspring, including reduced survival and decreased mean body weights at doses less than 0.2 times the MRHDID. In an embryo-fetal development study in pregnant rabbits, budesonide produced fetal loss, decreased fetal weight, and skeletal abnormalities at doses 0.5 times the MRHDID, while similar adverse fetal effects were observed in pregnant rats at doses approximately 5 times the MRHDID.

Lactation

Budesonide inhalation suspension is present in human milk; however, there are no available data on its effects on the breastfed child or on milk production. The developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for budesonide inhalation suspension and any potential adverse effects on the breastfed infant from the medication or from the underlying maternal condition.

Human data indicate that when budesonide is delivered via dry powder inhaler, 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.

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the lack of data necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population, although specific guidelines are not provided.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

The potential for acute toxic effects following an overdose of budesonide inhalation suspension is considered low. However, it is important for healthcare professionals to be aware of the implications of excessive dosing, particularly with prolonged use of inhaled corticosteroids.

Systemic Effects of Overdosage

In cases where inhaled corticosteroids are administered at excessive doses over an extended duration, patients may experience systemic corticosteroid effects. These effects can include hypercorticism, which is characterized by symptoms such as weight gain, hypertension, and glucose intolerance. Additionally, growth suppression may occur in pediatric patients, necessitating careful monitoring of growth parameters during treatment.

Recommended Actions

In the event of suspected overdosage, it is advisable for healthcare providers to assess the patient's clinical status and consider the potential for systemic effects. While acute toxicity is unlikely, ongoing evaluation and management may be warranted to mitigate any adverse effects associated with prolonged excessive dosing. Regular follow-up and patient education regarding the appropriate use of budesonide inhalation suspension are essential to prevent overdosage and its associated complications.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. Fertility and reproductive performance remained unaffected in rats at subcutaneous doses up to 80 mcg/kg, which is approximately equivalent to the maximum recommended human dose on a microgram per square meter (mcg/m²) basis. However, at subcutaneous doses of 20 mcg/kg and above, approximately 0.2 times the maximum recommended human dose in adults on a mcg/m² basis, there was a noted decrease in prenatal viability and viability of the pups at birth and during lactation, alongside a reduction in maternal body-weight gain. No adverse effects were recorded at a dose of 5 mcg/kg, which is approximately 0.05 times the maximum recommended human dose in adults on a mcg/m² basis.

In a two-year study involving Sprague-Dawley rats, budesonide resulted in a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg, approximately 0.5 and 0.1 times the maximum recommended human dose in adults and children aged 12 months to 8 years, respectively, on a mcg/m² basis. No tumorigenicity was observed in male rats at oral doses up to 25 mcg/kg, approximately 0.2 and 0.04 times the maximum recommended human dose in adults and children aged 12 months to 8 years, respectively, nor in female rats at oral doses up to 50 mcg/kg. In two additional two-year studies conducted in male Fischer and Sprague-Dawley rats, budesonide did not induce gliomas at an oral dose of 50 mcg/kg. However, a statistically significant increase in the incidence of hepatocellular tumors was noted in male Sprague-Dawley rats at the same oral dose. The concurrent reference corticosteroids, prednisolone and triamcinolone acetonide, exhibited similar findings in these studies.

In a 91-week study in mice, budesonide did not demonstrate any treatment-related carcinogenicity at oral doses up to 200 mcg/kg, which is approximately equivalent to and 0.1 times the maximum recommended human dose in adults and children aged 12 months to 8 years on a mcg/m² basis. Furthermore, budesonide was not found to be mutagenic or clastogenic in six different test systems, including the Ames Salmonella/microsome plate test, mouse micronucleus test, mouse lymphoma test, chromosome aberration test in human lymphocytes, sex-linked recessive lethal test in Drosophila melanogaster, and DNA repair analysis in rat hepatocyte culture.

Postmarketing Experience

Postmarketing experience has identified several adverse events associated with the use of budesonide inhalation suspension. Hypersensitivity reactions, including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm, have been reported. There is an observed increase in the risk of infections, particularly in patients with compromised immune systems due to the medication's effects.

Additionally, cases of adrenal insufficiency have been documented, characterized by symptoms such as fatigue, weakness, nausea, vomiting, and low blood pressure. A decrease in bone mineral density has also been noted, prompting healthcare providers to consider monitoring bone strength during treatment.

Concerns regarding growth have been raised, with reports of slowed or delayed growth in pediatric patients, necessitating regular growth assessments by healthcare providers. Furthermore, eye-related issues, including glaucoma and cataracts, have been reported, leading to recommendations for eye examinations during treatment. Lastly, instances of increased wheezing immediately following the administration of budesonide inhalation suspension have been observed.

Patient Counseling

Patients should be advised that budesonide inhalation suspension must be administered using a jet nebulizer connected to a compressor that provides adequate airflow, utilizing either a mouthpiece or a suitable face mask. It is important to inform patients that ultrasonic nebulizers are not appropriate for the administration of budesonide inhalation suspension and should not be used.

Patients should be made aware of the potential for localized infections with Candida albicans in the mouth and pharynx. If oropharyngeal candidiasis occurs, it should be treated with appropriate local or systemic antifungal therapy while continuing treatment with budesonide inhalation suspension. However, under close medical supervision, it may be necessary to temporarily interrupt therapy. Patients are encouraged to rinse their mouths after each inhalation to help mitigate this risk.

It is crucial to inform patients that budesonide inhalation suspension is not intended for the relief of acute asthma symptoms, and they should not use extra doses for this purpose. Acute symptoms should be managed with an inhaled, short-acting beta-agonist, such as albuterol. Patients should be instructed to notify their healthcare professional immediately if they notice a decrease in the effectiveness of their inhaled, short-acting beta-agonists, an increased need for inhalations, or a significant decline in lung function as defined by their physician.

Patients should not discontinue therapy with budesonide inhalation suspension without consulting their healthcare provider, as symptoms may recur following discontinuation. They should also be informed about the possibility of hypersensitivity reactions, including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm, and should discontinue use if any of these reactions occur.

For patients on immunosuppressant doses of corticosteroids, it is important to advise them to avoid exposure to chickenpox or measles and to seek medical advice promptly if exposure occurs. Additionally, patients should be informed that budesonide inhalation suspension may lead to systemic corticosteroid effects, such as hypercorticism and adrenal suppression. There have been reports of deaths due to adrenal insufficiency during and after transitioning from systemic corticosteroids, so patients should be counseled to taper off systemic corticosteroids slowly when switching to budesonide inhalation suspension.

Patients at increased risk for decreased bone mineral density should be made aware that the use of corticosteroids may further elevate this risk. Pediatric patients receiving orally inhaled corticosteroids, including budesonide inhalation suspension, may experience a reduction in growth velocity; therefore, healthcare professionals should monitor the growth of children and adolescents closely.

Long-term use of inhaled corticosteroids may also increase the risk of eye problems, such as cataracts or glaucoma, and regular eye examinations should be considered. Patients should be advised to use budesonide inhalation suspension consistently, either once or twice daily, as its effectiveness is contingent upon regular use. Maximum benefit may not be realized for 4 to 6 weeks or longer after initiating treatment, and patients should contact their healthcare professional if symptoms do not improve or worsen during this period.

For pediatric patients, it is recommended to rinse the mouth with water and spit it out after each treatment with budesonide inhalation suspension to reduce the risk of developing a fungal infection (thrush). If a child has been on long-term corticosteroids and is having their dose lowered or stopped, a warning card should be carried to indicate that the child may require corticosteroids during times of stress or in the event of an asthma attack that does not respond to bronchodilator medications.

Healthcare providers may need to monitor the child's blood, breathing, and conduct eye examinations while the child is using budesonide inhalation suspension.

Storage and Handling

Budesonide inhalation suspension is supplied in ampules and should be stored upright at a controlled room temperature of 20 to 25°C (68 to 77°F), ensuring protection from light. The product must not be frozen.

Once an envelope has been opened, the shelf life of the unused ampules is limited to 2 weeks, provided they are kept protected from light and returned to the aluminum foil envelope after opening. Any opened ampule should be used promptly. Prior to use, it is recommended to gently shake the ampule using a circular motion.

It is essential to keep this product out of reach of children.

Additional Clinical Information

Patients using budesonide inhalation suspension should be advised to rinse their mouths after each inhalation to minimize local side effects. It is crucial for patients to contact their physician immediately if they experience asthma episodes that do not respond to their usual bronchodilator doses during treatment.

Clinicians should be aware that patients previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be at increased risk for adrenal insufficiency when transitioning from systemic corticosteroids to inhaled corticosteroids. Patients are encouraged to carry a medical identification card indicating their potential need for supplementary systemic corticosteroids during periods of stress or severe asthma attacks. Additionally, those requiring oral corticosteroids should be weaned off slowly after starting budesonide inhalation suspension, with careful monitoring of lung function (FEV or AM PEF), beta-agonist use, and asthma symptoms during this withdrawal process.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Budesonide Inhalation as submitted by Lupin Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)