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 structural formula of budesonide is C25H34O6, with a molecular weight of 430.5.

Budesonide appears as a white or almost 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 single-dose ampule contains 1 mg of micronized budesonide in a 2 mL volume, along with inactive ingredients including citric acid monohydrate, disodium edetate, polysorbate 80, sodium chloride, tri-sodium citrate dihydrate, 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 from 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.

Limitations of Use: This drug is not indicated for the relief of acute bronchospasm.

Dosage and Administration

The initial dosing regimen should commence with the lowest recommended dose tailored to the specific treatment category. For bronchodilators, the recommended starting dose is 0.5 mg once daily or 0.25 mg twice daily. In the case of inhaled corticosteroids, the starting dose is also 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 of symptoms, it is recommended to increase the total daily dose and/or administer the dose in divided intervals. Once asthma stability is attained, the dosage should be titrated downwards to the lowest effective dose.

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

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 and acute asthma episodes.

Hypersensitivity reactions, including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm, have been reported. If any of these reactions occur, the use of budesonide inhalation suspension 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. 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 recommended to taper patients slowly from systemic corticosteroids to minimize this risk.

Hypercorticism and adrenal suppression may occur, particularly with very high dosages or in susceptible individuals at regular dosages. Should these changes occur, a gradual reduction of budesonide inhalation suspension is advised.

Long-term administration of budesonide inhalation suspension may lead to a reduction in bone mineral density. Therefore, it is essential 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 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 and Churg-Strauss syndrome in patients receiving budesonide inhalation suspension, as these conditions may arise during treatment.

To ensure patient safety, it is crucial to monitor the aforementioned parameters, including bone mineral density in at-risk patients, growth in pediatric patients, and the potential development of 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 crucial to discontinue 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 advised when prescribing to patients with these conditions, 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 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, 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 effects of growth suppression, including its impact on final adult height, 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, budesonide inhalation suspension should be discontinued, and alternative therapy should be instituted.

Lastly, eosinophilic conditions and Churg-Strauss syndrome should be considered, and vigilance is advised in recognizing these conditions. Notably, pneumonia was observed more frequently in pediatric patients treated with budesonide inhalation suspension compared to those receiving placebo.

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.

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 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 adrenal-axis function using an ACTH stimulation test. The results indicated no significant adrenal suppression in patients receiving budesonide inhalation suspension compared to placebo.

However, pneumonia was observed more frequently in patients treated with budesonide inhalation suspension than in those receiving placebo. Additionally, a dose-dependent effect on growth was noted; infants in the placebo group experienced an average growth of 3.7 cm over 12 weeks, while those receiving budesonide inhalation suspension showed average growths of 3.5 cm and 3.1 cm for the 0.5 mg and 1 mg doses, respectively. These findings suggest that the use of budesonide inhalation suspension in infants aged 6 to 12 months 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. The long-term implications of this reduction on final adult height remain unknown. Therefore, routine monitoring of growth in pediatric patients receiving inhaled corticosteroids, including budesonide inhalation suspension, is recommended, utilizing methods such as stadiometry. 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 collected from these trials indicate that there are 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 on the use of budesonide, the active ingredient in budesonide inhalation suspension, in pregnant women have not shown an increased risk of abnormalities when administered during pregnancy. A large population-based prospective cohort epidemiological study indicated no increased risk for congenital malformations from 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%, respectively). Additionally, the incidence of orofacial clefts among infants exposed to inhaled budesonide was comparable to the expected number in the normal population (4 children vs. 3.3, respectively).

In animal reproduction studies, budesonide administered by the subcutaneous route caused structural abnormalities, was embryocidal, and reduced fetal weights in rats and rabbits at doses less than the maximum recommended human daily inhalation dose (MRHDID). However, these 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, along with decreased maternal body-weight gain at doses 0.2 times the MRHDID. Furthermore, in embryo-fetal development studies, budesonide produced fetal loss, decreased fetal weight, and skeletal abnormalities in pregnant rabbits at doses 0.5 times the MRHDID, and similar adverse fetal effects in pregnant rats at doses approximately 5 times the MRHDID. Conversely, no structural abnormalities or embryocidal effects were seen in another study in pregnant rats 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. 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.

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 during pregnancy, healthcare professionals should weigh the benefits of asthma control against the potential risks of budesonide therapy in pregnant patients.

Lactation

Budesonide inhalation suspension is present in human milk; however, there are no available data on its effects on breastfed infants or on milk production in lactating mothers. 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 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 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

Acute toxic effects following an overdose of budesonide inhalation suspension are considered to be low. However, it is important for healthcare professionals to be aware of the potential consequences associated with excessive dosing.

In cases where inhaled corticosteroids are administered at high doses over extended periods, there is a risk of systemic corticosteroid effects. These may include hypercorticism, which is characterized by an excess of cortisol in the body, and growth suppression, particularly in pediatric patients.

Management of an overdose should focus on monitoring the patient for any signs of these systemic effects. If symptoms of hypercorticism or growth suppression are observed, appropriate clinical interventions should be initiated. It is advisable to consult relevant clinical guidelines and consider the patient's overall health status when determining the course of action.

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 inhalation 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.

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. 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 is an increased risk of infections due to immune system effects, as the medication may weaken the immune response.

Cases of adrenal insufficiency have been reported, with symptoms such as tiredness, weakness, nausea, vomiting, and low blood pressure. Monitoring for a decrease in bone mineral density is recommended, as this may occur during treatment.

Reports also indicate potential growth-related issues, necessitating regular monitoring of growth in pediatric patients. Furthermore, eye problems, including glaucoma and cataracts, have been noted, prompting healthcare providers to consider eye examinations during treatment.

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

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 advised to rinse their mouth 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 experience any of the following: a decrease in the effectiveness of inhaled, short-acting beta-agonists; an increased need for inhalations of inhaled, short-acting beta-agonists; 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 instructed to discontinue the medication if any such 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 be informed that budesonide inhalation suspension may lead to systemic corticosteroid effects, including hypercorticism and adrenal suppression. They should also 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 slowly from systemic corticosteroids 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. Furthermore, it is essential to inform patients 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 advised to use budesonide inhalation suspension 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 instructed to contact their healthcare professional.

Storage and Handling

The product is supplied in ampules, with specific storage and handling requirements to ensure its integrity and efficacy. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. The ampules must be kept upright and protected from light to maintain their quality.

Once the aluminum foil envelope is opened, the unused ampules have a shelf life of 2 weeks, provided they are returned to the envelope to shield them from light. Any opened ampule should be used promptly, and it is important to note that freezing is not permitted.

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 Teva Pharmaceuticals USA, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)