Budesonide

Description

Budesonide, USP, is the active ingredient in budesonide inhalation suspension, a corticosteroid chemically designated as (RS)-11β, 16α, 17, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione cyclic 16, 17-acetal with butyraldehyde. It is provided as a mixture of two epimers, 22R and 22S. The empirical formula of budesonide is C25H34O6, with a molecular weight of 430.53. Budesonide appears as a white to off-white crystalline 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.

Budesonide inhalation suspension is a sterile formulation intended for inhalation via jet nebulizer. Each ampule contains 0.5 mg of micronized budesonide in a total volume of 2 mL, along with inactive ingredients including disodium edetate, sodium chloride, sodium citrate, citric acid, polysorbate 80, and water for injection. The delivery of the active ingredient 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 adequate 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 medication is not indicated for the relief of acute bronchospasm.

There are no teratogenic or nonteratogenic effects associated with the use of budesonide inhalation suspension.

Dosage and Administration

The recommended dosing for bronchodilators is 0.5 mg once daily or 0.25 mg twice daily. For inhaled corticosteroids, the dosing 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. Oral corticosteroids can be administered at a dose of 0.5 mg twice daily or 1 mg once daily. In symptomatic children who do not respond to non-steroidal therapy, a starting dose of 0.25 mg once daily may be considered.

If once-daily treatment does not provide adequate control of symptoms, the total daily dose should be increased and/or administered as a divided dose. Once asthma stability is achieved, it is recommended to titrate the dose downwards to the lowest effective dose.

The medication is intended for inhalation use only, utilizing compressed air-driven jet nebulizers. It is important to note that this medication is not suitable for injection and should not be used with ultrasonic devices.

Contraindications

Use of this product is contraindicated in the following situations:

Patients requiring primary treatment for status asthmaticus or other acute episodes of asthma that necessitate intensive measures. Additionally, individuals with a known hypersensitivity to any of the ingredients in budesonide should not use this product, as it may lead to severe allergic reactions.

Warnings and Precautions

Localized infections, particularly Candida albicans infections of the mouth and throat, may occur in patients using budesonide. 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 is not indicated for the relief of acute bronchospasm; therefore, its use in the management of acute asthma episodes is contraindicated.

Hypersensitivity reactions, including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm, have been reported in patients using budesonide. Should any of these reactions occur, budesonide must be discontinued immediately.

Immunosuppression is a potential concern with budesonide, 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 to these patients, as they may experience a more severe or even fatal course of chickenpox or measles.

When transferring patients from systemic corticosteroid therapy to budesonide, 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 with very high dosages of budesonide or at standard dosages in susceptible individuals. If such changes are observed, a gradual reduction in budesonide dosage is recommended.

Long-term administration of budesonide may lead to a reduction in bone mineral density. Therefore, it is crucial 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 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 has been reported with budesonide use. If this occurs, the medication should be discontinued, and alternative therapy should be initiated.

Healthcare professionals should remain vigilant for eosinophilic conditions and Churg-Strauss syndrome in patients receiving budesonide, as these conditions may arise during treatment.

To ensure patient safety, it is recommended to monitor bone mineral density in patients with major risk factors, track the growth of pediatric patients, and conduct close monitoring for glaucoma and cataracts throughout the duration of budesonide therapy.

Side Effects

Most common adverse reactions observed in patients include respiratory infections, rhinitis, coughing, otitis media, viral infections, moniliasis, gastroenteritis, vomiting, diarrhea, abdominal pain, ear infections, epistaxis, conjunctivitis, and rash.

Localized infections, particularly Candida albicans infections of the mouth and throat, may occur. It is recommended to monitor patients periodically for signs of adverse effects on the oral cavity and to advise them to rinse their mouths following inhalation.

Patients should not use budesonide for the relief of acute bronchospasm, as it may lead to deterioration of disease and acute asthma episodes. Hypersensitivity reactions, including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm, have been reported. Discontinuation of budesonide is advised if such reactions occur.

Immunosuppression is a potential risk, which may worsen existing infections such as tuberculosis, fungal, bacterial, viral, or parasitic infections, as well as ocular herpes simplex. Caution is warranted when using budesonide 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, there is a risk of impaired adrenal function. It is essential to taper patients slowly from oral steroids to mitigate this risk. Hypercorticism and adrenal suppression may occur with very high dosages or at regular dosages in susceptible individuals; if such changes are observed, a gradual reduction of budesonide is recommended.

Long-term administration of budesonide 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 budesonide treatment.

Patients should also be monitored for the development of glaucoma and cataracts. In the event of paradoxical bronchospasm, budesonide should be discontinued, and alternative therapy should be instituted.

Eosinophilic conditions, including Churg-Strauss syndrome, should be considered, and vigilance is advised. While the potential for acute toxic effects following an overdose of budesonide is low, excessive doses used for prolonged periods may lead to systemic corticosteroid effects such as hypercorticism or growth suppression. Notably, pneumonia was observed more frequently in pediatric patients treated with budesonide compared to those receiving placebo.

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.

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, 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 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 adrenal-axis function using an ACTH stimulation test. The mean changes from baseline indicated no adrenal suppression in patients receiving budesonide compared to placebo; however, individual cases showed that 7 patients (6 in the budesonide groups and 1 in the placebo group) experienced a shift from normal to subnormal stimulated cortisol levels by Week 12.

Pneumonia occurred more frequently in patients treated with budesonide, with 2 cases in the 0.5 mg group, 1 in the 1 mg group, and none in the placebo group. A dose-dependent effect on growth was observed, with infants in the placebo arm experiencing an average growth of 3.7 cm over 12 weeks, compared to 3.5 cm and 3.1 cm in the budesonide 0.5 mg and 1 mg arms, respectively. These findings suggest that budesonide use in infants aged 6 to 12 months may lead to systemic effects, consistent with growth suppression noted in other studies involving 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 (ranging from 0.3 to 1.8 cm per year), which appears related to dose and duration of exposure. The long-term implications of this 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 a dose of 200 mcg twice daily experienced a 1.1-centimeter reduction in growth compared to those receiving placebo at the end of one year. Routine monitoring of growth in pediatric patients receiving inhaled corticosteroids, including budesonide, is recommended. The potential growth effects of prolonged treatment should be carefully weighed against the clinical benefits and the 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, 30% of the 215 patients studied were aged 65 years or older, with 10% being 75 years of age or older. Despite the inclusion of these elderly patients, no overall differences in safety were observed when compared to younger patients. Additionally, other clinical and medical surveillance experiences have not identified any significant differences in responses between geriatric patients and their younger counterparts.

Given the lack of observed differences in safety profiles, specific dosage adjustments for elderly patients are not warranted based solely on age. However, healthcare providers should remain vigilant in monitoring geriatric patients for any potential adverse effects, as individual responses may vary. It is essential to consider the overall health status and comorbidities of elderly patients when prescribing budesonide, ensuring that treatment is tailored to their specific needs.

Pregnancy

There are no adequate well-controlled studies of budesonide in pregnant women; however, published studies indicate that inhaled budesonide does not increase the risk of abnormalities when administered during pregnancy. The results from a large population-based prospective cohort epidemiological study show no increased risk for congenital malformations associated with the use of inhaled budesonide during early pregnancy, with rates of recorded congenital malformations being similar to those in the general population (3.8% vs. 3.5%). Additionally, the incidence of orofacial clefts among infants born to mothers exposed to inhaled budesonide was comparable to the expected number in the normal population (4 children vs. 3.3).

Animal reproduction studies have demonstrated 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. In an embryo-fetal development study in pregnant rabbits, budesonide resulted in fetal loss, decreased fetal weight, and skeletal abnormalities at doses 0.5 times the MRHDID. Similarly, in pregnant rats, adverse fetal effects were noted at doses approximately 5 times the MRHDID, while no structural abnormalities or embryocidal effects were seen at doses approximately 2 times the MRHDID.

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 during labor and delivery. While budesonide has not been shown to affect delivery, it has been associated with reduced offspring survival and decreased mean body weights at birth and during lactation at doses less than 0.2 times the MRHDID and higher. Given these findings, healthcare professionals should weigh the potential risks and benefits of budesonide use in pregnant patients, particularly those with asthma, and consider close monitoring throughout pregnancy.

Lactation

Budesonide is excreted in human milk; however, there are no adequate well-controlled studies of budesonide in nursing mothers. The effects of budesonide on breastfed infants and on milk production are unknown. Caution should be exercised when administering budesonide to lactating mothers.

In a peri-and post-natal development study, budesonide did not affect delivery outcomes; however, it did impact the growth and development of offspring. Specifically, there were observed reductions in offspring survival and decreased mean body weights at birth and during lactation at doses less than 0.2 times the maximum recommended human daily intake (MRHDID).

Renal Impairment

There is no specific information 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 absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

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 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 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. Additionally, growth suppression may occur in pediatric patients, necessitating careful monitoring of growth parameters in this population.

Recommended Actions

In the event of suspected overdose, it is advisable to assess the patient for any signs of systemic corticosteroid effects. While acute toxicity is unlikely, ongoing evaluation and management may be warranted based on the duration and extent of the overdose. Healthcare professionals should consider consulting a poison control center or a clinical toxicologist for further guidance on management strategies tailored to the individual patient's needs.

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 intravenous 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 oral 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.

A 91-week study in mice revealed no treatment-related carcinogenicity at oral doses up to 200 mcg/kg, which is approximately equivalent to and 0.1 times the MRHDID in adults and children aged 12 months to 8 years on a mcg/m² basis.

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 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. Additionally, a decrease in maternal body weight gain was noted at these doses, while no such effects were recorded at 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. There have also been observations of immune system effects, with an increased likelihood of infections noted in patients receiving treatment. Symptoms indicative of infection may include fever, pain, aches, chills, fatigue, nausea, and vomiting; it is advised that healthcare providers be informed of any such symptoms during the use of budesonide inhalation suspension.

Cases of adrenal insufficiency have been reported, characterized by insufficient production of steroid hormones by the adrenal glands. Symptoms may include fatigue, weakness, nausea, vomiting, and low blood pressure. Additionally, a decrease in bone mineral density has been observed, prompting healthcare providers to consider monitoring bone strength during treatment.

Reports of slowed or delayed growth in pediatric patients have also been noted, suggesting the need for regular growth assessments by healthcare providers while using budesonide inhalation suspension. Furthermore, eye problems, including glaucoma and cataracts, have been documented, leading to recommendations for eye examinations during treatment.

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

Patient Counseling

Patients should be advised that budesonide 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 effective administration of budesonide 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 budesonide therapy. However, under close medical supervision, it may be necessary to temporarily interrupt budesonide treatment. Patients are encouraged to rinse their mouths after inhalation to help mitigate this risk.

It is crucial to inform patients that budesonide 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 experience any of the following: decreasing effectiveness of inhaled, short-acting beta2-agonists; an increased need for inhalations of inhaled, short-acting beta2-agonists; or a significant decrease in lung function as defined by their physician.

Patients should not discontinue budesonide therapy without consulting their healthcare provider, as symptoms may recur following discontinuation. They should also be informed about the risk of hypersensitivity reactions, including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm, which have been reported with budesonide use. If any of these reactions occur, patients should discontinue budesonide and seek medical attention.

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 been properly vaccinated, they should consult their physician without delay. Patients should also be informed of the potential for worsening existing infections, including tuberculosis, fungal, bacterial, viral, or parasitic infections, as well as ocular herpes simplex.

Patients should be advised that budesonide may lead to systemic corticosteroid effects, such as hypercorticism and adrenal suppression. They should be made aware 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.

For patients at increased risk for decreased bone mineral density, it is important to highlight 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.

Patients should be advised that long-term use of inhaled corticosteroids may increase the risk of certain eye problems, such as cataracts or glaucoma, and that regular eye examinations should be considered. Furthermore, patients should be instructed to use budesonide at regular intervals, either once or 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 directed to contact their healthcare professional.

Storage and Handling

Budesonide inhalation suspension is supplied in ampules that should be stored upright at a temperature range of 20° to 25°C (68° to 77°F) and must be protected from light. Once the aluminum foil pouch is opened, the shelf life of the unused ampules is limited to 2 weeks, provided they are returned to the pouch to shield them from light. It is essential that any opened ampule is used promptly. Prior to use, the ampule should be gently shaken using a circular motion. Freezing of the product is strictly prohibited.

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 resume oral corticosteroids in large doses during periods of stress or severe asthma attacks and to seek further instructions from their physicians. A gradual weaning from systemic corticosteroids is recommended after switching to budesonide. Clinicians should monitor lung function (FEV or AM PEF), beta-agonist use, and asthma symptoms closely during the withdrawal of oral corticosteroids. Patients should also be vigilant for signs of adrenal insufficiency, including fatigue, weakness, nausea, vomiting, and hypotension, and carry a medical identification card indicating their potential need for supplementary systemic corticosteroids during stressful situations or severe asthma attacks.

FDA Insert (PDF)

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

View full prescribing information (PDF)