Budesonide

Description

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

Budesonide appears as a white or almost white crystalline powder that is practically insoluble in water and sparingly soluble in alcohol, with a partition coefficient between octanol and water at pH 7.4 of 1.6 x 10^3. The inhalation suspension is a sterile, off-white aqueous formulation intended for administration via a jet nebulizer. Each suspension contains micronized budesonide USP along with inactive ingredients, including edetate disodium, sodium chloride, sodium citrate, citric acid monohydrate, polysorbate 80, and Water for Injection.

Budesonide inhalation suspension is available in three dose strengths in single-dose ampules: 0.25 mg/2 mL, 0.5 mg/2 mL, and 1 mg/2 mL. The amount of budesonide delivered to the lungs is influenced by patient-specific factors, the type of jet nebulizer used, and the performance of the compressor. Under in vitro conditions using the Pari-LC-Jet Plus Nebulizer/Pari Master compressor system, the mean delivered dose at the mouthpiece was 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 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 dosing can be set at 0.5 mg twice daily or 1 mg once 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, 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.

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 the primary treatment of status asthmaticus or other acute episodes of asthma that require intensive measures. Additionally, it is contraindicated in patients with a known hypersensitivity to any of the ingredients in the formulation.

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 mouth following inhalation to mitigate this risk.

Budesonide inhalation suspension is not indicated for the relief of acute bronchospasm. Caution should be exercised to avoid its use in such situations, as it may lead to deterioration of the disease or acute asthma episodes.

Hypersensitivity reactions, including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm, have been reported. Should any of these reactions occur, the use of budesonide inhalation suspension must 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. The use of budesonide inhalation suspension in these patients should be approached with caution, as there is a risk of a more serious or even fatal course of chickenpox or measles in susceptible individuals.

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 at regular dosages in susceptible individuals. If such changes are observed, 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 this regard.

Paradoxical bronchospasm has been reported with the use of budesonide inhalation suspension. If this occurs, the medication should be discontinued, and alternative therapy should be instituted.

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

To ensure patient safety, it is recommended to monitor patients with major risk factors for decreased bone mineral content, as well as to monitor the growth of pediatric patients and conduct close monitoring for glaucoma and cataracts.

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. Additionally, there is a potential for immunosuppression, which may lead to a worsening of existing infections, including tuberculosis, fungal, bacterial, viral, or parasitic infections, as well as ocular herpes simplex. Caution is warranted in patients with these infections, as a more serious or even fatal course of chickenpox or measles can occur in susceptible individuals.

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. Furthermore, hypercorticism and adrenal suppression may occur, particularly with very high dosages or at regular dosages 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, necessitating monitoring in patients with major risk factors for decreased bone mineral content. Additionally, the growth of pediatric patients should be closely monitored, as a dose-dependent effect on growth has been noted, with reductions in growth velocity associated with inhaled corticosteroids. The long-term implications of this reduction in growth velocity remain unknown.

Patients should also be monitored for the development of glaucoma and cataracts, as close observation is warranted in these cases. Paradoxical bronchospasm has been reported; if this occurs, it is advised to discontinue budesonide inhalation suspension and consider alternative therapies.

Lastly, pneumonia was observed more frequently in pediatric patients treated with budesonide compared to those receiving placebo, highlighting the need for careful consideration of the risk-benefit profile in this population. Eosinophilic conditions and Churg-Strauss syndrome should also be monitored, as patients may present with these conditions during treatment.

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 enhanced corticosteroid effects is recommended when these agents are used together. No specific dosage adjustments are provided; however, clinicians should consider the potential for increased effects and adjust the corticosteroid dosage 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 in pediatric patients aged six months to 12 months have been evaluated but not established. In contrast, safety and effectiveness have been established in children aged 12 months to 8 years. A 12-week study involving 141 pediatric patients aged 6 to 12 months with mild to moderate asthma or recurrent/persistent wheezing indicated that infants in the placebo arm experienced an average growth of 3.7 cm, compared to 3.5 cm and 3.1 cm in the budesonide 0.5 mg and 1 mg arms, respectively. These findings suggest that the use of budesonide in infants may lead to systemic effects, consistent with growth suppression observed in other studies involving inhaled corticosteroids.

Controlled clinical studies have demonstrated that inhaled corticosteroids can result in a reduction in growth velocity among pediatric patients. The mean reduction in growth velocity was approximately one centimeter per year, with a range of 0.3 to 1.8 cm per year, and this effect appears to be dose- and duration-dependent. The long-term implications of this reduction in growth velocity, including its potential impact on final adult height, remain unknown.

In a study involving asthmatic children aged 5 to 12 years, those treated with budesonide via a dry powder inhaler at a dose of 200 mcg twice daily exhibited a 1.1-centimeter reduction in growth compared to those receiving placebo after one year. Therefore, routine monitoring of growth in pediatric patients receiving inhaled corticosteroids, including budesonide inhalation suspension, is recommended, utilizing methods such as stadiometry. To mitigate systemic effects, it is advised that each patient be titrated to the lowest effective dose of inhaled corticosteroids.

Geriatric Use

In clinical trials involving budesonide, 30% of the 215 adult patients studied were aged 65 years or older, with 10% being 75 years or older. Despite the inclusion of these elderly patients, no overall differences in safety were observed when compared to younger patients. Furthermore, additional clinical and medical surveillance has not revealed any significant differences in responses between geriatric patients and their younger counterparts.

Given the lack of observed differences in safety and efficacy, specific dosage adjustments for elderly patients are not warranted. However, healthcare providers should remain vigilant in monitoring this population, as individual responses may vary. It is advisable to consider the overall health status and comorbidities of geriatric patients when prescribing budesonide, ensuring that any potential risks are adequately managed.

Pregnancy

There are no adequate well-controlled studies of budesonide in pregnant women. However, published studies have not shown that inhaled budesonide increases the risk of abnormalities when administered during pregnancy. 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.

In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes, including preeclampsia in the mother and 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.

Animal reproduction studies have indicated that budesonide can cause structural abnormalities, is embryocidal, and reduces 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. In a fertility and reproduction study, budesonide resulted in decreased prenatal viability and viability in pups at birth and during lactation at doses 0.2 times the MRHDID. Additionally, an embryo-fetal development study in pregnant rabbits demonstrated fetal loss, decreased fetal weight, and skeletal abnormalities at doses 0.5 times the MRHDID. Conversely, another embryo-fetal development study in pregnant rats did not reveal structural abnormalities or embryocidal effects at doses approximately 2 times the MRHDID.

Studies indicate no increased risk for congenital malformations from the use of inhaled budesonide during early pregnancy. The rate of recorded congenital malformations among infants whose mothers were exposed to inhaled budesonide during early pregnancy was similar to the general population rate (3.8% vs. 3.5%). Furthermore, the incidence of orofacial clefts in infants after exposure to inhaled budesonide was comparable to the expected number in the normal population (4 children vs. 3.3).

There are no well-controlled human studies investigating the effects of budesonide inhalation suspension during labor and delivery. Given the potential risks associated with poorly controlled asthma, healthcare professionals should weigh the benefits of budesonide therapy against the potential risks to the fetus when prescribing this medication to 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 may experience altered pharmacokinetics of budesonide due to its predominant hepatic metabolism. Although formal pharmacokinetic studies have not been conducted in this population, it is important to note that impairment of liver function may lead to an accumulation of budesonide in plasma.

Consequently, patients with hepatic disease should be closely monitored for potential adverse effects and therapeutic efficacy. Dosage adjustments may be necessary based on the clinical judgment of the healthcare provider, taking into account the degree of hepatic impairment and the patient's overall health status. Regular assessment of liver function is recommended to ensure safe and effective use of budesonide in this patient population.

Overdosage

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

Systemic Effects of Prolonged Overdose

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

Recommended Actions

In the event of suspected overdose, it is advisable to monitor the patient for any signs of systemic corticosteroid effects. While acute toxicity is unlikely, healthcare providers should remain vigilant and consider the patient's overall clinical picture. If symptoms of hypercorticism or growth suppression are observed, appropriate management strategies should be implemented, which may include dose adjustment or discontinuation of the medication, depending on the severity of the symptoms and the clinical judgment of the healthcare provider.

Overall, while the risk of acute toxic effects from budesonide overdose is low, awareness and monitoring for potential systemic effects are essential in managing patient safety.

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 0.04 times the MRHDID) and in female rats at doses up to 50 mcg/kg.

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. 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 unaffected in rats administered subcutaneous doses of budesonide 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 adverse 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

Hypersensitivity reactions, including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm, have been reported following the use of budesonide inhalation suspension. There have also been observations of immune system effects, indicating a potential increased risk of infections in patients receiving treatment that may weaken the immune system.

Cases of adrenal insufficiency have been documented, characterized by insufficient production of steroid hormones by the adrenal glands. Additionally, a decrease in bone mineral density has been reported, prompting healthcare providers to consider monitoring bone strength during treatment with budesonide inhalation suspension.

Reports of slowed or delayed growth in pediatric patients have emerged, suggesting the need for regular growth assessments by healthcare providers during the course of treatment. Furthermore, eye-related issues, including glaucoma and cataracts, have been noted, leading to recommendations for eye examinations while using the medication.

Increased wheezing immediately following the administration of budesonide inhalation suspension has also been reported.

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, equipped with 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 risk of localized infections with Candida albicans in the mouth and pharynx, which have been reported in some individuals. 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, under close medical supervision, it may be necessary to temporarily interrupt the use of budesonide inhalation suspension. Patients are advised 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 experience 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 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. Additionally, hypersensitivity reactions, including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm, have been reported. Patients should discontinue the use of budesonide inhalation suspension 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, they should consult their physician without delay, especially if the child has not had chickenpox or has not been properly vaccinated.

Patients should be informed about the potential for worsening existing infections, including tuberculosis, fungal, bacterial, viral, or parasitic infections, as well as ocular herpes simplex. They should also be made aware that budesonide inhalation suspension may lead to systemic corticosteroid effects, such as hypercorticism and adrenal suppression. It is essential to inform patients that there have been reports of deaths 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 should be advised that the use of corticosteroids may further elevate this risk. Additionally, it should be communicated that orally inhaled corticosteroids, including budesonide inhalation suspension, 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, either once or twice daily, 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 contact their healthcare professional.

Patients should be advised to rinse their child’s mouth with water and have them spit it out after each treatment with budesonide inhalation suspension, avoiding swallowing the water to reduce the risk of developing a fungal infection (thrush) in the mouth. If a child has been on long-term corticosteroids and the dose is being reduced or stopped, a warning card should be carried to indicate that the child may require corticosteroids during times of stress or during 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 temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° and 30°C (59° and 86°F). It is essential to protect the product from light to maintain its efficacy.

Once the aluminum foil pouch is opened, the shelf life of the unused ampules is limited to 2 weeks, provided they are kept protected from light by returning them to the pouch. Any opened ampule must be used promptly to ensure proper dosing. Prior to use, the ampule should be gently shaken using a circular motion.

It is crucial to keep this medication out of reach of children and to avoid freezing the product to maintain its integrity.

Additional Clinical Information

Patients using budesonide should rinse their mouth after 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. Those who have previously been maintained on 20 mg or more per day of prednisone (or its equivalent) may be particularly susceptible to adrenal insufficiency when transitioning from systemic corticosteroids to inhaled corticosteroids.

Patients are advised to carry a medical identification card indicating the potential need for supplementary systemic corticosteroids during periods of stress or severe asthma attacks. Additionally, for patients requiring oral corticosteroids, a gradual weaning from systemic corticosteroid use is recommended after switching to budesonide inhalation suspension. Clinicians should closely monitor lung function (FEV or AM PEF), beta-agonist use, and asthma symptoms during the withdrawal of oral corticosteroids.

FDA Insert (PDF)

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

View full prescribing information (PDF)