Budesonide

Uses and Indications

Budesonide is indicated for various conditions, primarily involving inflammatory bowel diseases and asthma management.

Crohn's Disease

Budesonide capsules (enteric coated and delayed-release) are indicated for:

• Treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon in patients 8 years and older.

• Maintenance of clinical remission of mild to moderate Crohn's disease involving the ileum and/or the ascending colon for up to 3 months in adults.

Ulcerative Colitis

Budesonide extended-release tablets and UCERIS (rectal foam) are indicated for:

• Induction of remission in patients with active, mild to moderate ulcerative colitis.

Asthma

Budesonide inhalation suspension, Pulmicort, and Pulmicort Respules are indicated for:

• Maintenance treatment of asthma and as prophylactic therapy in children 12 months to 8 years of age.

• PULMICORT FLEXHALER is also indicated for the maintenance treatment of asthma as prophylactic therapy in adult and pediatric patients six years of age or older.

Limitations of Use

Budesonide is not indicated for the relief of acute bronchospasm in asthma patients.

Eosinophilic Esophagitis

EOHILIA is indicated for 12 weeks of treatment in adult and pediatric patients 11 years of age and older with eosinophilic esophagitis (EoE). It has not been shown to be safe and effective for the treatment of EoE for longer than 12 weeks.

Kidney Function

TARPEYO is indicated to reduce the loss of kidney function in adults with primary immunoglobulin A nephropathy (IgAN) who are at risk for disease progression.

Dosage and Administration

The recommended dosage and administration of Budesonide varies based on the formulation and indication.

Budesonide Capsules (Enteric Coated and Delayed Release): For the treatment of mild to moderate active Crohn's disease, adults are advised to take 9 mg once daily in the morning for up to 8 weeks, with the option to repeat 8-week treatment courses for recurring episodes. Pediatric patients aged 8 to 17 years who weigh more than 25 kg should also take 9 mg once daily for up to 8 weeks, followed by a taper to 6 mg once daily for an additional 2 weeks. For maintenance of clinical remission, adults should take 6 mg once daily for up to 3 months, followed by a taper to complete cessation after this period, as continued treatment beyond 3 months has not shown substantial clinical benefit. When transitioning from oral prednisolone, it is recommended to begin tapering prednisolone concurrently with the initiation of Budesonide. In adult patients with moderate hepatic impairment (Child-Pugh Class B), a dosage reduction to 3 mg once daily should be considered.

Administration Instructions: Budesonide capsules should be swallowed whole and not chewed or crushed. For patients unable to swallow intact capsules, the contents may be mixed with one tablespoonful of applesauce and consumed within 30 minutes, followed by 8 ounces of water. Grapefruit juice should be avoided during therapy.

Budesonide Inhalation (Aerosol and Suspension): For patients aged 18 years and older, the recommended starting dosage is 360 mcg twice daily, with a maximum dosage not exceeding 720 mcg twice daily. For patients aged 6 to 17 years, the starting dosage is 180 mcg twice daily, with a maximum of 360 mcg twice daily. The inhalation formulation is intended for oral inhalation only and should be administered via compressed air-driven jet nebulizers, not for injection.

Budesonide Rectal Foam: The recommended dosage is 1 metered dose administered twice daily for the first 2 weeks, followed by 1 metered dose once daily for the subsequent 4 weeks. The canister should be warmed in the hands and shaken vigorously for 10 to 15 seconds prior to use.

Budesonide Tablets (Extended Release): For the induction of remission in adult patients with active, mild to moderate ulcerative colitis, the recommended dosage is one 9 mg tablet taken once daily in the morning, with or without food, for up to 8 weeks.

Budesonide Suspension: For inhalation use, the starting dose should be based on previous therapy, with options including 0.5 mg once daily or 0.25 mg twice daily for bronchodilators, and similar dosing for inhaled corticosteroids. If once-daily treatment does not provide adequate control, the total daily dose may be increased or administered as a divided dose. Once asthma stability is achieved, the dose should be titrated downwards.

All formulations should be used as directed, and healthcare professionals should monitor patients for efficacy and any potential side effects during treatment.

Contraindications

Hypersensitivity to budesonide or any of the ingredients in budesonide formulations is a contraindication for use. This includes hypersensitivity reactions to milk proteins in specific products such as Pulmicort.

Budesonide is contraindicated for the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. This applies to all forms of budesonide, including inhalation suspensions, aerosols, and rectal foams.

In summary, the use of budesonide is contraindicated in patients with known hypersensitivity to its components and in situations requiring immediate intensive asthma treatment.

Warnings and Precautions

Hypercorticism and Adrenal Axis Suppression Budesonide may cause hypercorticism and adrenal axis suppression. Patients, particularly pediatrics and those with hepatic impairment, should be monitored for signs and symptoms. Tapering is recommended upon discontinuation.

Symptoms of Steroid Withdrawal Patients transitioning from other systemic corticosteroids may experience withdrawal symptoms. It is essential to taper slowly from corticosteroids with high systemic effects and monitor for unmasking of allergies, such as rhinitis and eczema.

Increased Risk of Infection Budesonide is associated with an increased risk of infections, including serious and potentially fatal varicella and measles. Patients with active or quiescent tuberculosis, untreated fungal, bacterial, systemic viral, or parasitic infections, or ocular herpes simplex should be closely monitored. Avoid use in patients with fungal infections, Strongyloides infestation, cerebral malaria, and ocular herpes simplex. Screening for hepatitis B infection is advised.

Localized Infections Candida albicans infections of the mouth and throat may occur. Patients should be monitored periodically for signs of adverse effects on the oral cavity and advised to rinse their mouth following inhalation.

Deterioration of Disease and Acute Episodes Budesonide should not be used for the relief of acute bronchospasm or during rapidly deteriorating asthma episodes. Immediate re-evaluation is required in such cases.

Hypersensitivity Reactions Anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported. Discontinue budesonide if such reactions occur.

Immunosuppression Budesonide may worsen existing infections. Caution is advised in patients with a history of tuberculosis, fungal, bacterial, viral, or parasitic infections. Serious or fatal outcomes from chickenpox or measles can occur in susceptible individuals.

Transferring Patients from Systemic Corticosteroids There is a risk of impaired adrenal function when transferring patients from systemic corticosteroids. Tapering is necessary to mitigate this risk.

Reduction in Bone Mineral Density Long-term administration of budesonide may lead to a reduction in bone mineral density. Patients with major risk factors for decreased bone mineral content should be monitored.

Effects on Growth Pediatric patients should have their growth monitored during treatment with budesonide.

Glaucoma and Cataracts Close monitoring for glaucoma and cataracts is warranted during treatment.

Paradoxical Bronchospasm If paradoxical bronchospasm occurs, budesonide should be discontinued, and alternative therapy should be instituted.

Eosinophilic Conditions and Churg-Strauss Syndrome Healthcare providers should be alert to eosinophilic conditions, including Churg-Strauss syndrome, in patients receiving budesonide.

General Precautions No specific general precautions are listed; however, patients should be informed about the potential risks associated with budesonide therapy.

Laboratory Tests Regular monitoring for bone mineral density, growth in pediatric patients, and close observation for glaucoma and cataracts is recommended. Screening for hepatitis B infection should also be conducted.

Emergency Medical Help Instructions Patients should seek emergency medical help if they experience hypersensitivity reactions or paradoxical bronchospasm.

Side Effects

Most common adverse reactions reported in clinical trials (≥5% incidence) include:

• Headache

• Respiratory infection

• Nausea

• Back pain

• Dyspepsia

• Dizziness

• Abdominal pain

• Flatulence

• Vomiting

• Fatigue

• Pain

Serious Adverse Reactions

• Hypercorticism and Adrenal Axis Suppression: May occur with treatment; patients, especially pediatrics and those with hepatic impairment, should be monitored for signs and symptoms.

• Immunosuppression and Increased Risk of Infection: Increased risk of viral, bacterial, fungal, protozoal, and helminthic infections, including potentially fatal varicella and measles. Patients should be monitored for new or worsening infections, and drug discontinuation should be considered. Avoid use in patients with active or quiescent tuberculosis, untreated fungal infections, Strongyloides infestation, cerebral malaria, and ocular herpes simplex. Screening for hepatitis B infection is recommended.

• Symptoms of Steroid Withdrawal: Patients transferred from systemic corticosteroids with high systemic effects should be tapered slowly to avoid withdrawal symptoms and unmasking of allergies (e.g., rhinitis, eczema).

• Kaposi’s Sarcoma: Reported in patients receiving corticosteroid therapy, particularly for chronic conditions.

Localized Infections

• Candida albicans infection of the mouth and throat may occur. Patients should be advised to rinse the mouth following inhalation to minimize this risk.

Hypersensitivity Reactions

• Anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported. Discontinue treatment if such reactions occur.

Other Notable Adverse Reactions

• Deterioration of Asthma or Acute Episodes: Budesonide should not be used for the relief of acute symptoms; patients require immediate re-evaluation during rapidly deteriorating asthma.

• Reduction in Bone Mineral Density: Long-term administration may lead to decreased bone mineral content; monitor patients with major risk factors.

• Effects on Growth: Pediatric patients should be monitored for growth velocity, as inhaled corticosteroids may cause reductions in growth.

• Glaucoma and Cataracts: Close monitoring is warranted for patients at risk.

• Paradoxical Bronchospasm: Discontinue therapy and consider alternative treatment if this occurs.

Additional Information

• Acute toxicity and/or death following overdose of glucocorticoids are rare, but treatment should consist of immediate gastric lavage or emesis followed by supportive care.

• Hypoadrenalism may occur in infants born to mothers receiving corticosteroids during pregnancy; these infants should be observed for signs of hypoadrenalism.

• Reports of pneumonia were observed more frequently in pediatric patients treated with budesonide compared to placebo.

• A dose-dependent effect on growth velocity has been noted in pediatric patients, with reductions associated with inhaled corticosteroids. The long-term effects of this reduction in growth velocity are unknown.

Drug Interactions

CYP3A4 inhibitors, including strong agents such as ketoconazole and ritonavir, can significantly affect the pharmacokinetics of budesonide. The concomitant use of these inhibitors may lead to increased systemic concentrations of budesonide, which can enhance the risk of systemic corticosteroid effects. Therefore, it is advised to avoid the use of CYP3A4 inhibitors, particularly ketoconazole and grapefruit juice, with all formulations of budesonide, including capsules, delayed release pellets, aerosols, and suspensions.

For formulations of budesonide that are particularly sensitive to CYP3A4 inhibition, such as Pulmicort (aerosol and powder) and Uceris (aerosol and foam), caution is emphasized when used alongside strong CYP3A4 inhibitors. The potential for increased systemic corticosteroid effects necessitates careful monitoring and consideration of alternative therapies.

In summary, the following interactions are noted:

• CYP3A4 Inhibitors (e.g., ketoconazole, grapefruit juice):

  • Can increase systemic budesonide concentrations; avoid concomitant use with all budesonide formulations.

• Strong CYP3A4 Inhibitors (e.g., ritonavir):

  • Use with caution as they may cause increased systemic corticosteroid effects; this applies to all budesonide formulations, including inhalants and suspensions.

No specific drug and laboratory test interactions have been provided for budesonide, but the aforementioned interactions should be carefully considered in clinical practice.

Pediatric Use

The safety and effectiveness of budesonide have been established in pediatric patients aged 8 to 17 years who weigh more than 25 kg for the treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon. However, the safety and effectiveness of budesonide have not been established in pediatric patients less than 8 years of age or for the maintenance of clinical remission of Crohn's disease. An open-label study conducted in pediatric patients aged 5 to 17 years did not establish the safety and efficacy of budesonide for maintenance treatment.

Inhaled budesonide has been evaluated in children aged 6 to 17 years, with efficacy results similar to those observed in adults. Controlled clinical studies indicate that inhaled corticosteroids, including budesonide, may cause a reduction in growth velocity in pediatric patients, with a mean reduction of approximately one centimeter per year. This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure than some commonly used tests of HPA-axis function. The long-term effects of this reduction in growth velocity, including the impact on final adult height, are unknown, and the potential for "catch up" growth following discontinuation of treatment has not been adequately studied.

In a 12-week study involving 141 pediatric patients aged 6 to 12 months with mild to moderate asthma or recurrent/persistent wheezing, a dose-dependent effect on growth was noted. Infants in the placebo arm experienced 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. Pneumonia was observed more frequently in patients treated with budesonide than in those receiving placebo.

The growth of pediatric patients receiving inhaled corticosteroids, including budesonide, should be monitored routinely (e.g., via stadiometry). To minimize the systemic effects of inhaled corticosteroids, each patient should be titrated to the lowest effective dose. Additionally, children treated with corticosteroids by any route may experience a decrease in growth velocity, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of alternative treatment options.

Geriatric Use

Clinical studies of budesonide formulations, including capsules, inhalation suspensions, and rectal foams, have not included sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Among the patients treated in these studies, a small percentage (3% or 17 out of 651) were aged 65 or older, with none exceeding 74 years of age. In inhalation studies, 30% of participants were 65 years or older, and 10% were 75 years or older, yet no overall differences in safety were observed between elderly and younger patients.

Other clinical experience has not identified significant differences in responses between elderly and younger patients. However, due to the greater frequency of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies, dose selection for elderly patients should be approached with caution. It is generally recommended to start at the low end of the dosing range for this population.

Pregnancy

Limited published studies report on the use of budesonide in pregnant patients; however, the data are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, subcutaneous administration of budesonide during organogenesis in pregnant rats and rabbits resulted in increased fetal loss, decreased pup weights, and skeletal abnormalities. Maternal toxicity was observed at these dose levels. Based on animal data, healthcare providers should advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage in the U.S. general population is approximately 2% to 4% and 15% to 20%, respectively. All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. Some epidemiological studies suggest that increased disease activity in women with conditions such as Crohn's disease or ulcerative colitis is associated with adverse pregnancy outcomes, including preterm delivery and low birth weight infants. Pregnant women with these conditions should be counseled on the importance of disease control.

Hypoadrenalism may occur in infants born to mothers receiving corticosteroids during pregnancy. Infants should be carefully monitored for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting, and managed accordingly.

Budesonide has been shown to be teratogenic and embryolethal in animal studies. In embryo-fetal development studies, adverse effects on fetal development and survival were observed at doses approximately 0.5 times the maximum recommended human dose (MRHD) in rats and 0.05 times the MRHD in rabbits. Maternal toxicity, including reduced body weight gain, was noted at these doses. In peri- and post-natal development studies, budesonide did not affect delivery but did impact offspring growth and development, resulting in reduced survival and decreased mean body weights at birth and during lactation at doses as low as 0.02 times the MRHD.

While studies of pregnant women have not shown that inhaled budesonide increases the risk of congenital abnormalities when administered during pregnancy, caution is advised, particularly in women with poorly controlled asthma, as they may face increased risks of perinatal adverse outcomes.

Lactation

Budesonide is excreted in human milk, although specific lactation studies on oral formulations, including capsules and delayed-release pellets, have not been conducted. The effects of budesonide on breastfed infants and milk production remain unclear. However, one published study indicates that budesonide is present in human milk following maternal inhalation, with infant doses estimated to be approximately 0.3% to 1% of the maternal weight-adjusted dosage. The milk/plasma ratio for budesonide has been reported to range between 0.4 and 0.5.

No adverse events were noted in breastfed infants following maternal use of inhaled budesonide, and plasma concentrations of the drug were not detected. Despite this, the developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for budesonide and any potential adverse effects on the infant from either the drug or the underlying maternal condition.

For oral budesonide formulations, the recommended daily dose can be significantly higher (up to 9 mg) compared to inhaled budesonide (up to 800 mcg). Consequently, assuming a constant coefficient of extrapolation between inhaled and oral doses, budesonide exposure to nursing children may be up to 10 times higher with oral administration than with inhalation.

Caution is advised when administering budesonide to nursing mothers, and routine monitoring of infant growth is recommended, particularly with chronic use. Additionally, signs of hypoadrenalism should be observed in infants born to mothers receiving corticosteroids during pregnancy.

Renal Impairment

Patients with renal impairment do not have specific dosage adjustments, monitoring requirements, or safety considerations outlined for the use of budesonide in its various formulations, including capsules, delayed release pellets, aerosols, powders, and suspensions. The available data across multiple labels indicate a lack of information regarding the impact of reduced kidney function on the pharmacokinetics or safety profile of budesonide. Consequently, healthcare providers should exercise caution and consider individual patient factors when prescribing budesonide to patients with renal impairment, as the absence of specific guidance necessitates a careful assessment of potential risks and benefits.

Hepatic Impairment

Patients with moderate to severe hepatic impairment (Child-Pugh Class B and C) may experience an increased risk of hypercorticism and adrenal axis suppression due to elevated systemic exposure to budesonide. Therefore, the use of budesonide is not recommended in patients with severe hepatic impairment (Child-Pugh Class C).

For patients with moderate hepatic impairment (Child-Pugh Class B), it is advised to monitor for signs and symptoms of hypercorticism and consider dosage reduction. In contrast, no dosage adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A).

Additionally, patients with hepatic impairment should be closely monitored for potential immunosuppression and an increased risk of infections, including viral, bacterial, fungal, protozoal, and helminthic infections. Monitoring for new or worsening infections is essential, and discontinuation of budesonide should be considered if such infections arise.

Formal pharmacokinetic studies of budesonide in patients with hepatic impairment have not been conducted, but it is known that budesonide is predominantly cleared by hepatic metabolism, indicating that liver function impairment may lead to plasma accumulation of the drug.

Overdosage

In the event of an overdose of budesonide, reports of acute toxicity and/or death are rare. Management of overdose should include immediate gastric lavage or emesis, followed by supportive and symptomatic therapy.

Acute overdose may lead to symptoms such as decreased motor activity, piloerection, and generalized edema, particularly noted in animal studies where single oral doses of 200 mg/kg and 400 mg/kg were lethal in female and male mice, respectively. Chronic overdosage, especially when corticosteroids are used at excessive doses for prolonged periods, may result in systemic effects such as hypercorticism and adrenal axis suppression. In cases of severe disease requiring continuous steroid therapy, it may be appropriate to temporarily reduce the dosage.

For inhaled formulations, the potential for acute toxic effects is considered low, and instances of acute overdose often remain asymptomatic. However, excessive doses administered over extended periods can still lead to systemic corticosteroid effects, including hypercorticism and growth suppression. Monitoring for these effects is advised in patients receiving high doses of inhaled corticosteroids.

Overall, while the risk of severe toxicity is low, careful management and monitoring are essential in cases of suspected overdose.

Nonclinical Toxicology

Teratogenic Effects

No teratogenic effects have been reported in the studies conducted with budesonide.

Impairment of Fertility

Budesonide did not affect fertility or reproductive performance in rats at subcutaneous doses up to 80 mcg/kg, which is approximately 0.07 times the maximum recommended human dose on a body surface area basis. However, at subcutaneous doses of 20 mcg/kg and above (approximately 0.02 times the maximum recommended human dose), there was a decrease in prenatal viability and viability of pups at birth and during lactation, along with a reduction in maternal body weight gain. No such effects were observed at a dose of 5 mcg/kg (approximately 0.005 times the maximum recommended human dose).

Carcinogenesis

Carcinogenicity studies of budesonide were performed in both rats and mice. In a two-year study involving Sprague-Dawley rats, a statistically significant increase in the incidence of gliomas was observed in male rats at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). Additionally, increased incidences of primary hepatocellular tumors were noted in male rats at doses of 25 mcg/kg (approximately 0.023 times the maximum recommended human dose) and higher. No tumorigenicity was observed in female rats at oral doses up to 50 mcg/kg. In further studies, budesonide did not induce gliomas in male Sprague-Dawley rats at the same dose, but it did cause a statistically significant increase in hepatocellular tumors at 50 mcg/kg. The concurrent reference corticosteroids, prednisolone and triamcinolone acetonide, exhibited similar findings. In a 91-week study in mice, no treatment-related carcinogenicity was observed at oral doses up to 200 mcg/kg (approximately 0.1 times the maximum recommended human dose).

Mutagenesis

Budesonide was not found to be mutagenic or clastogenic in various test systems, including the Ames test, mouse lymphoma cell forward gene mutation test, human lymphocyte chromosome aberration test, Drosophila melanogaster sex-linked recessive lethality test, rat hepatocyte unscheduled DNA synthesis test, and mouse micronucleus test.

Storage and Handling

Budesonide is supplied in various forms including capsules, delayed release pellets, inhalation suspensions, aerosols, and tablets. The following outlines the storage and handling requirements for these products:

Storage Conditions

• Budesonide capsules and coated pellets should be stored at 20°C to 25°C (68°F to 77°F), with excursions permitted between 15°C to 30°C (59°F to 86°F). Containers must be kept tightly closed.

• Budesonide inhalation suspensions, including Pulmicort and Uceris, should be stored upright at controlled room temperature of 20°C to 25°C (68°F to 77°F) and protected from light. Any opened ampule must be used promptly, and the shelf life of unused ampules is 2 weeks when protected.

• Aerosol forms of Budesonide, such as Uceris and Pulmicort, should also be stored at 20°C to 25°C (68°F to 77°F) with similar temperature excursions allowed. These products must not be exposed to heat or stored above 120°F (49°C) and should not be refrigerated.

• Budesonide suspensions must be stored upright and protected from light. After opening the aluminum foil envelope, unused vials or ampules should be returned to the envelope to maintain protection from light.

• Tablets, including film-coated and extended-release forms, should be stored at 20°C to 25°C (68°F to 77°F) and kept tightly closed, protected from light and moisture.

Handling Requirements

• All Budesonide products should be kept out of the reach of children.

• For inhalation suspensions, gently shake the ampule using a circular motion before use.

• Aerosol products contain flammable propellants; therefore, they should not be exposed to fire, flame, or smoking during and immediately following administration. The canister should not be burned after use, and contents should not be punctured or incinerated.

These guidelines ensure the integrity and efficacy of Budesonide products throughout their shelf life.