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, 22R and 22S. The empirical formula of budesonide is C25H34O6, and it has a molecular weight of 430.5. The structural formula is represented as follows:

Budesonide appears as a white or almost white crystalline powder that is practically insoluble in water, sparingly soluble in ethanol, and freely soluble in methylene chloride. It is also characterized as a white to off-white, tasteless, and odorless powder, with a partition coefficient between octanol and water at pH 7.4 of 1.6 x 10^3.

Budesonide inhalation suspension is formulated as a sterile suspension intended for inhalation via jet nebulizer. Each ampule contains micronized budesonide along with inactive ingredients, including citric acid, edetate disodium dihydrate, polysorbate 80, sodium chloride, sodium citrate, and water for injection. The product is available in two dose strengths: 0.25 mg and 0.5 mg per 2 mL ampule.

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 indicate 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 patients utilizing bronchodilators alone, the starting dose is 0.5 mg once daily or 0.25 mg administered twice daily. Inhaled corticosteroids may be initiated at 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 those requiring oral corticosteroids, the recommended starting 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, it is advised to increase the total daily dose and/or to administer the dose in divided intervals. Once asthma stability is attained, a gradual titration downwards of the dose is recommended.

Administration should be conducted via inhalation using compressed air-driven jet nebulizers exclusively; this formulation is not intended for injection and should not be utilized with ultrasonic devices.

Contraindications

Use of budesonide inhalation suspension is contraindicated in patients with hypersensitivity to any of its ingredients. Additionally, it should not be used as the primary treatment for status asthmaticus or other acute episodes of asthma that require intensive measures.

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. It is advisable to instruct patients to rinse their mouths following inhalation to mitigate this risk.

Budesonide inhalation suspension is not indicated for the relief of acute bronchospasm. Therefore, healthcare providers should refrain from using this medication in the management of acute asthma episodes or any deterioration of the disease.

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

Immunosuppression is a potential concern with the use of budesonide inhalation suspension, 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 this medication to such patients, as there is a risk of a more serious or even fatal course of infections like chickenpox or measles in susceptible individuals.

When transferring patients from systemic corticosteroids 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 at standard dosages. If these changes are observed, it is important to reduce the dosage of budesonide inhalation suspension gradually.

Long-term administration of budesonide inhalation suspension may lead to a reduction in bone mineral density. Therefore, healthcare professionals should 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 also be monitored for the development of glaucoma and cataracts, as these conditions may arise during treatment.

In the event of paradoxical bronchospasm, it is crucial to discontinue budesonide inhalation suspension and consider alternative therapeutic options.

Finally, healthcare providers should remain vigilant for eosinophilic conditions, including Churg-Strauss syndrome, in patients receiving budesonide inhalation suspension.

Side Effects

Patients receiving budesonide inhalation suspension may experience a range of adverse reactions, which can be categorized by seriousness and frequency.

Most common adverse reactions include respiratory infections, rhinitis, coughing, otitis media, viral infections, moniliasis, gastroenteritis, vomiting, diarrhea, abdominal pain, ear infections, epistaxis, conjunctivitis, and rash. These reactions were observed in clinical trials and may vary in incidence among patients.

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 advised to rinse their mouths following inhalation to mitigate this risk.

Serious adverse reactions include hypersensitivity reactions such as anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm. If any of these reactions occur, it is advised to discontinue the use of budesonide inhalation suspension immediately.

Patients may also experience immunosuppression, which can lead to a worsening of existing infections, including tuberculosis, fungal, bacterial, viral, or parasitic infections, as well as ocular herpes simplex. Caution is warranted when prescribing budesonide inhalation suspension to patients with these conditions. Additionally, there is a risk of a more serious or even fatal course of chickenpox or measles in susceptible individuals.

When transferring patients from systemic corticosteroids 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. If such changes are observed, a gradual reduction of budesonide inhalation suspension is recommended.

Long-term administration of budesonide inhalation suspension may lead to a reduction in bone mineral density; therefore, patients with major risk factors for decreased bone mineral content should be monitored closely. Furthermore, the growth of pediatric patients should be monitored, as a dose-dependent effect on growth has been noted, with reductions in growth velocity associated with inhaled corticosteroids.

Close monitoring for glaucoma and cataracts is warranted in patients receiving this treatment.

Paradoxical bronchospasm has been reported; if this occurs, it is crucial to discontinue budesonide inhalation suspension and consider alternative therapies.

Eosinophilic conditions, including Churg-Strauss syndrome, should be monitored for in patients receiving this medication.

In pediatric patients, pneumonia was observed more frequently in those treated with budesonide inhalation suspension compared to those receiving placebo. This highlights the importance of careful monitoring in this population.

Drug Interactions

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

Monitoring for signs of increased corticosteroid effects is recommended when these agents are used together. No specific dosage adjustments are provided; however, clinicians should consider the potential for enhanced effects and adjust treatment accordingly based on the patient's clinical response.

Packaging & NDC

The table below lists all NDC Code configurations of Budesonide, 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, which indicated no significant adrenal suppression in the budesonide groups compared to placebo. However, individual assessments revealed 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 placebo at one year. Routine monitoring of growth in pediatric patients receiving inhaled corticosteroids, including budesonide inhalation suspension, is recommended. The potential growth effects of prolonged treatment should be carefully weighed against the clinical benefits and risks associated with alternative therapies. 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. Additionally, other clinical and medical surveillance experiences have 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 shown that inhaled budesonide increases the risk of abnormalities when administered during pregnancy. A large population-based prospective cohort study indicated no increased risk for congenital malformations from the use of inhaled budesonide during early pregnancy, with the rate of recorded congenital malformations among infants whose mothers used inhaled budesonide for asthma in early pregnancy being similar to the general population rate (3.8% vs. 3.5%). Additionally, the number of infants born with orofacial clefts after exposure to inhaled budesonide was comparable to the expected number in the normal population (4 children vs. 3.3).

In animal reproduction studies, budesonide has been associated with structural abnormalities, embryocidal effects, and reduced fetal weights in rats and rabbits at doses less than the maximum recommended human daily inhalation dose (MRHDID). Specifically, 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. Conversely, in another study involving pregnant rats, no structural abnormalities or embryocidal effects were observed at doses approximately 2 times the MRHDID.

The estimated background risk of major birth defects and miscarriage in the U.S. general population is 2% to 4% and 15% to 20%, respectively. It is important to note that women with poorly or moderately controlled asthma are at an increased risk for 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 that have investigated the effects of budesonide inhalation suspension during labor and delivery. Given the potential risks associated with poorly controlled asthma during pregnancy, healthcare professionals should weigh the benefits of asthma control against the potential risks of budesonide use in pregnant patients.

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

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring of these patients.

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.

In cases where inhaled corticosteroids are administered at excessive doses over an extended duration, systemic corticosteroid effects may manifest. These effects can include hypercorticism, which is characterized by symptoms such as weight gain, hypertension, and glucose intolerance, as well as growth suppression in pediatric patients.

Management of an overdose should focus on monitoring the patient for any signs of systemic corticosteroid effects. If symptoms of hypercorticism or growth suppression are observed, appropriate interventions should be initiated. This may involve adjusting the dosage of the inhaled corticosteroid or considering alternative therapeutic options to mitigate the risk of adverse effects.

Healthcare professionals are advised to provide supportive care and to consult relevant clinical guidelines for the management of corticosteroid-related complications in the event of an overdose.

Nonclinical Toxicology

In a two-year study conducted in Sprague-Dawley rats, budesonide was associated with a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg, which corresponds to approximately 0.5 and 0.1 times the maximum recommended human daily intake dose (MRHDID) 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 0.06 times the MRHDID) and in female rats at doses up to 50 mcg/kg (approximately 0.4 and 0.1 times the MRHDID).

In two additional two-year studies involving male Fischer and Sprague-Dawley rats, budesonide did not induce gliomas at an oral dose of 50 mcg/kg (approximately 0.4 and 0.1 times the MRHDID). However, a statistically significant increase in the incidence of hepatocellular tumors was noted in male Sprague-Dawley rats at the same dose. The concurrent reference corticosteroids, prednisolone and triamcinolone acetonide, exhibited similar findings in these studies. In a separate 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 MRHDID.

Budesonide was evaluated for mutagenicity and clastogenicity 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. The results indicated that budesonide was neither mutagenic nor clastogenic.

Fertility and reproductive performance were not adversely affected in rats at subcutaneous doses up to 80 mcg/kg, which is approximately equivalent to the MRHDID in adults on a mcg/m² basis. However, a decrease in prenatal viability and viability of pups at birth and during lactation was observed at subcutaneous doses of 20 mcg/kg and above, approximately 0.2 times the MRHDID. No such effects were noted at a dose of 5 mcg/kg, which corresponds to approximately 0.05 times the MRHDID in adults on a mcg/m² basis.

Postmarketing Experience

Postmarketing experience has identified several adverse events associated with the use of budesonide inhalation suspension, reported voluntarily or through surveillance programs.

Hypersensitivity reactions, including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm, have been documented. Additionally, there are reports of immune system effects, indicating an increased likelihood of infections in patients receiving treatment that may weaken the immune system.

Cases of adrenal insufficiency have been noted, characterized by insufficient production of steroid hormones by the adrenal glands. Symptoms associated with this condition include fatigue, weakness, nausea, vomiting, and low blood pressure.

There is also evidence of a decrease in bone mineral density, which may warrant monitoring by healthcare providers during treatment. Concerns regarding slowed or delayed growth in pediatric patients have been raised, suggesting the need for regular growth assessments.

Eye-related issues, such as glaucoma and cataracts, have been reported, prompting healthcare providers to recommend eye examinations during the course of treatment.

Increased wheezing immediately following the administration of budesonide inhalation suspension has been observed, highlighting the importance of having a fast-acting inhaled bronchodilator available for the management of sudden wheezing episodes.

The most frequently reported side effects include respiratory infections, runny nose, cough, viral infections, gastroenteritis, ear infections, nosebleeds, conjunctivitis, and rash.

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. In the event that oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic antifungal therapy while continuing therapy with budesonide inhalation suspension. However, there may be instances where therapy with budesonide inhalation suspension needs to be temporarily interrupted under close medical supervision. Patients are encouraged to rinse their mouths after inhalation to help mitigate this risk.

It is crucial to inform patients that budesonide inhalation suspension is not intended to relieve 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 any of the following: a decrease in the effectiveness of inhaled, short-acting beta-agonists; an increased need for inhalations of these medications; or a significant decrease 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. Additionally, hypersensitivity reactions, including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm, have been reported with the use of budesonide inhalation suspension. Patients should be advised to discontinue the medication if any of these reactions occur.

For patients on immunosuppressant doses of corticosteroids, it is important to warn them to avoid exposure to chickenpox or measles. If exposure occurs, especially in children who have not had chickenpox or have not been properly vaccinated, they should consult their physician without delay. Patients should also be informed about the potential for worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, as well as ocular herpes simplex.

Patients should be made aware that budesonide inhalation suspension may lead to systemic corticosteroid effects, including hypercorticism and adrenal suppression. They should be informed that there have been fatalities due to adrenal insufficiency during and after transitioning from systemic corticosteroids. Therefore, patients should taper off systemic corticosteroids slowly when switching to budesonide inhalation suspension.

Patients at increased risk for decreased bone mineral density (BMD) should be advised that the use of corticosteroids may further elevate this risk. Additionally, patients should be informed that orally inhaled corticosteroids, including budesonide, may reduce growth velocity in pediatric patients. Healthcare professionals should closely monitor the growth of children and adolescents receiving corticosteroids by any route.

Long-term use of inhaled corticosteroids may increase the risk of certain eye problems, such as cataracts or glaucoma; therefore, regular eye examinations should be considered. Patients should be instructed to use budesonide inhalation suspension at regular intervals, specifically twice a day, as its effectiveness is contingent upon consistent use. Maximum benefit may not be realized for 4 to 6 weeks or longer after initiating treatment. If symptoms do not improve within this timeframe or if the condition worsens, patients should be advised to contact their healthcare professional.

Storage and Handling

Budesonide inhalation suspension is supplied in ampules, with specific storage and handling requirements to ensure product integrity and efficacy. It should be stored upright at a controlled room temperature of 20°C to 25°C (68°F to 77°F) and must be protected from light.

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 to maintain effectiveness. Prior to use, the ampule should be gently shaken using a circular motion.

It is essential to keep this product out of reach of children and to avoid freezing to preserve its quality.

Additional Clinical Information

Patients using budesonide inhalation suspension should be advised to rinse their mouths after each inhalation to minimize potential 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.

Additionally, patients who have previously been 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. Therefore, it is recommended that these patients carry a medical identification card indicating their need for supplementary systemic corticosteroids during times of stress or severe asthma attacks.

FDA Insert (PDF)

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

View full prescribing information (PDF)