Budesonide

Description

Budesonide, the active ingredient of budesonide delayed-release capsules, is a synthetic corticosteroid. It is chemically designated as (RS)-11β, 16α, 17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde and is provided as a mixture of two epimers (22R and 22S). The empirical formula of budesonide is C25H34O6, and its molecular weight is 430.5 g/mol. Budesonide appears as a white to off-white, tasteless, odorless 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 5 is 1.6 x 10^3 at ionic strength 0.01.

Budesonide delayed-release capsules are formulated as hard gelatin capsules filled with enteric-coated granules that dissolve at pH greater than 5.5. Each capsule for oral administration contains 3 mg of micronized budesonide, along with inactive ingredients including ethylcellulose, acetyltributyl citrate, methacrylic acid copolymer type C, triethyl citrate, antifoam M, polysorbate 80, talc, and sugar spheres. The capsule shells contain gelatin, iron oxide, and titanium dioxide.

Uses and Indications

This drug is indicated for the treatment of mild to moderate active Crohn’s disease involving the ileum and/or the ascending colon in patients aged 8 years and older. Additionally, it is indicated for the maintenance of clinical remission of mild to moderate Crohn’s disease involving the ileum and/or the ascending colon for a duration of up to 3 months in adults.

There are no teratogenic or nonteratogenic effects associated with this drug.

Dosage and Administration

Patients should take the medication once daily in the morning. The capsules must be swallowed whole; they should not be chewed or crushed. For patients who are unable to swallow an intact capsule, the capsules may be opened, and the granules can be emptied onto one tablespoonful of applesauce. The mixture should be thoroughly mixed and consumed within 30 minutes without chewing or crushing the granules. It is recommended to follow this with 8 ounces of water. Patients should avoid the consumption of grapefruit juice throughout the duration of therapy.

For the treatment of mild to moderate active Crohn’s disease, the recommended dosage is as follows:

• Adults: 9 mg once daily for up to 8 weeks. If necessary, repeat the 8-week treatment course for recurring episodes of active disease.

• Pediatrics (ages 8 to 17 years) weighing more than 25 kg: 9 mg once daily for up to 8 weeks, followed by a reduced dosage of 6 mg once daily in the morning for an additional 2 weeks.

For the maintenance of clinical remission of mild to moderate Crohn’s disease, the recommended dosage is:

• Adults: 6 mg once daily for up to 3 months, with a taper to complete cessation after this period. Continued treatment beyond 3 months has not demonstrated substantial clinical benefit.

• When transitioning from oral prednisolone, it is advised to begin tapering prednisolone concurrently with the initiation of budesonide delayed-release capsules.

In patients with moderate hepatic impairment (Child-Pugh Class B), consideration should be given to reducing the dosage to 3 mg once daily.

Contraindications

Use of budesonide delayed-release capsules is contraindicated in patients with hypersensitivity to budesonide or any of the excipients contained in the formulation. This contraindication is based on the potential for severe allergic reactions in susceptible individuals.

Warnings and Precautions

Hypercorticism and adrenal axis suppression may occur during treatment. Healthcare professionals should closely monitor patients for signs and symptoms of these conditions, particularly in pediatric populations and individuals with hepatic impairment, who may be at an increased risk.

When transitioning patients from other systemic corticosteroids, it is essential to taper the dosage slowly, especially for those on corticosteroids with high systemic effects. Monitoring for withdrawal symptoms is crucial, as well as being vigilant for the unmasking of allergies, such as rhinitis and eczema.

Patients receiving corticosteroid therapy are at an increased risk of immunosuppression, which can lead to a heightened susceptibility to various infections, including viral, bacterial, fungal, protozoal, and helminthic infections. This risk encompasses potentially fatal infections such as varicella and measles. Healthcare providers should monitor patients for any new or worsening infections and consider discontinuation of the drug if necessary. It is advised to avoid the use of this therapy in patients with existing fungal infections, Strongyloides infestation, cerebral malaria, and ocular herpes simplex. Additionally, screening for hepatitis B infection is recommended prior to initiating treatment.

Kaposi’s sarcoma has been reported in patients undergoing corticosteroid therapy, particularly those being treated for chronic conditions.

Furthermore, healthcare professionals should monitor patients with concomitant conditions that may exacerbate the unwanted effects of corticosteroids, such as hypertension and diabetes mellitus, to ensure safe and effective management of their treatment.

Side Effects

Patients receiving budesonide delayed-release capsules may experience a range of adverse reactions. The most common adverse reactions, occurring in 5% or more of patients, include headache, respiratory infection, nausea, back pain, dyspepsia, dizziness, abdominal pain, flatulence, vomiting, fatigue, and pain.

Serious adverse reactions may include hypercorticism and adrenal axis suppression, which can occur with treatment. It is essential to monitor patients for signs and symptoms of these conditions, particularly in pediatric patients and those with hepatic impairment, who may be at increased risk. Additionally, patients transitioning from other systemic corticosteroids should be tapered slowly to avoid withdrawal symptoms and the unmasking of allergies, such as rhinitis and eczema.

Immunosuppression is another significant concern, as patients may face an increased risk of infections, including viral, bacterial, fungal, protozoal, and helminthic infections. This includes potentially fatal infections such as varicella and measles. Patients should be monitored for new or worsening infections, and consideration should be given to discontinuing the drug if such infections arise. Budesonide delayed-release capsules should be avoided in patients with active fungal infections, Strongyloides infestation, cerebral malaria, and ocular herpes simplex. Screening for hepatitis B infection is also recommended.

Kaposi’s sarcoma has been reported in patients receiving corticosteroid therapy, particularly those treated for chronic conditions. Furthermore, it is important to monitor patients with concomitant conditions, such as hypertension and diabetes mellitus, where corticosteroids may have unwanted effects.

Hypersensitivity reactions to budesonide or any of its ingredients have been noted. Additionally, systemic corticosteroids, including budesonide, may lead to a reduction in growth velocity in pediatric patients. Notably, pediatric patients with Crohn’s disease exhibit a 17% higher mean systemic exposure and cortisol suppression compared to adult patients with the same condition.

Drug Interactions

CYP3A4 inhibitors, such as ketoconazole and grapefruit juice, have the potential to significantly increase systemic concentrations of budesonide. Co-administration of these agents is not recommended due to the risk of enhanced effects and potential adverse reactions associated with elevated budesonide levels. It is advisable to avoid the use of budesonide in conjunction with these CYP3A4 inhibitors to ensure patient safety and therapeutic efficacy. Monitoring for signs of increased budesonide effects may be warranted if exposure to these inhibitors cannot be avoided.

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

The safety and effectiveness of budesonide delayed-release capsules 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 these capsules have not been established in pediatric patients under 8 years of age for the same condition.

Additionally, the safety and effectiveness of budesonide delayed-release capsules for the maintenance of clinical remission in pediatric patients with mild to moderate Crohn’s disease remain unestablished. An open-label study aimed at evaluating the safety and tolerability of budesonide as maintenance treatment in pediatric patients aged 5 to 17 years did not demonstrate the safety and efficacy of maintaining clinical remission.

It is important to note that systemic corticosteroids, including budesonide delayed-release capsules, may lead to a reduction in growth velocity in pediatric patients. Furthermore, pediatric patients with Crohn’s disease exhibit a 17% higher mean systemic exposure and cortisol suppression compared to adults with the same condition.

Geriatric Use

Clinical studies of budesonide delayed-release capsules did not include a sufficient number of patients aged 65 years and older to determine whether they respond differently from younger patients. Among the 651 patients treated with budesonide delayed-release capsules in these studies, only 17 patients (3%) were aged 65 years or older, and none were older than 74 years.

While other reported clinical experiences have not identified significant differences in responses between elderly patients and younger patients, caution is advised in the dose selection for geriatric patients. It is generally recommended to start at the low end of the dosing range for elderly patients, taking into account the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies. Monitoring for potential adverse effects and therapeutic efficacy is essential in this population.

Pregnancy

Limited published studies report on the use of budesonide in pregnant women; however, the data are insufficient to inform a drug-associated risk for major birth defects and miscarriage. Clinical considerations should be taken into account when prescribing this medication to pregnant patients.

Animal reproduction studies have demonstrated that administration of subcutaneous budesonide during organogenesis in pregnant rats and rabbits resulted in increased fetal loss, decreased pup weights, and skeletal abnormalities at doses approximately 0.5 times and 0.05 times the maximum recommended human dose, respectively. Maternal toxicity was also observed in both species at these dose levels. Based on these animal data, healthcare professionals should advise pregnant women of the potential risks to the fetus associated with budesonide use.

The estimated background risk of major birth defects and miscarriage in the general population is unknown; however, all pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Epidemiological studies indicate an association between adverse pregnancy outcomes and women with Crohn’s disease, particularly during periods of increased disease activity, which may include preterm birth and low birth weight infants. Therefore, pregnant women with Crohn’s disease should be counseled on the importance of disease control.

Additionally, 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 an embryo-fetal development study involving pregnant rats, administration of budesonide during the period of organogenesis resulted in adverse effects on fetal development and survival at doses up to approximately 500 mcg/kg. Similarly, in pregnant rabbits, dosing during organogenesis led to increased maternal abortion rates and adverse effects on fetal development at doses up to approximately 25 mcg/kg. Maternal toxicity, including reduced body weight gain, was noted at lower doses in both species.

In a peri-and post-natal development study, budesonide did not affect delivery but did impact the growth and development of offspring, with reduced survival and decreased mean body weights observed at exposures of 0.02 times the maximum recommended human dose. These findings occurred alongside maternal toxicity.

Healthcare professionals should weigh the potential risks and benefits of budesonide use in pregnant patients and consider alternative therapies when appropriate.

Lactation

Lactation studies have not been conducted with oral budesonide, including budesonide delayed-release capsules, and no information is available on the effects of the drug on the breastfed infant or on milk production. However, one published study indicates that budesonide is present in human milk following maternal inhalation, resulting in infant doses approximately 0.3% to 1% of the maternal weight-adjusted dosage, with a milk/plasma ratio ranging between 0.4 and 0.5.

Budesonide plasma concentrations were not detected, and no adverse events were noted in breastfed infants following maternal use of inhaled budesonide. It is important to consider the developmental and health benefits of breastfeeding alongside the mother’s clinical need for budesonide delayed-release capsules and any potential adverse effects on the breastfed infant from the capsules or from the underlying maternal condition.

The recommended daily dose of budesonide delayed-release capsules is higher (up to 9 mg daily) compared to inhaled budesonide (up to 800 mcg daily) used in the aforementioned study. Assuming the coefficient of extrapolation between inhaled and oral doses is constant across all dose levels, budesonide exposure to the nursing child at therapeutic doses of budesonide delayed-release capsules may be up to 10 times higher than that from inhaled budesonide.

Renal Impairment

Patients with renal impairment have no specific information regarding dosage adjustments, special monitoring, or safety considerations provided in the text. Therefore, healthcare professionals should exercise caution and consider individual patient factors when prescribing to this population. Regular assessment of renal function may be warranted to ensure safe and effective use of the medication in patients with reduced kidney function.

Hepatic Impairment

Patients with hepatic impairment may experience hypercorticism and adrenal axis suppression as a result of treatment. It is essential to monitor these patients for signs and symptoms indicative of these conditions, as they may be at an increased risk, particularly in pediatric populations.

Additionally, patients with compromised liver function are at an elevated risk of immunosuppression, which can lead to an increased susceptibility to various infections, including viral, bacterial, fungal, protozoal, and helminthic infections. This includes potentially fatal infections such as varicella and measles. Continuous monitoring for new or worsening infections is recommended, and consideration should be given to discontinuing the drug if such infections arise.

Furthermore, the use of this treatment is contraindicated in patients with active fungal infections, Strongyloides infestation, cerebral malaria, and ocular herpes simplex. It is also advised to screen for hepatitis B infection prior to initiating therapy in patients with hepatic impairment.

Overdosage

Acute toxicity and fatalities associated with glucocorticoid overdosage are infrequently reported. In the event of an overdose, immediate intervention is critical. Recommended actions include performing gastric lavage or inducing emesis, followed by supportive and symptomatic therapy to manage the patient's condition effectively.

Experimental data indicate that single oral doses of 200 mg/kg in female mice and 400 mg/kg in male mice resulted in lethality. Observed signs of acute toxicity in these studies included decreased motor activity, piloerection, and generalized edema, which may serve as indicators of severe adverse effects in humans as well.

Prolonged use of corticosteroids at excessive doses can lead to systemic effects, including hypercorticism and suppression of the adrenal axis. Healthcare professionals should monitor patients closely for these potential complications and manage them accordingly.

Nonclinical Toxicology

Budesonide has been evaluated for its potential teratogenic effects, and no teratogenic effects were observed in the studies conducted.

In terms of non-teratogenic effects, studies in rats indicated that budesonide did not affect fertility 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 (approximately 0.02 times the maximum recommended human dose on a body surface area basis) and above, there was a noted decrease in prenatal viability and viability of pups at birth and during lactation, alongside a reduction in maternal body-weight gain. No such adverse effects were observed at a dose of 5 mcg/kg (approximately 0.005 times the maximum recommended human dose on a body surface area basis).

Carcinogenicity studies involving budesonide were conducted in both rats and mice. In a two-year study with 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 on a body surface area basis) and higher. No tumorigenicity was detected in female rats at oral doses up to 50 mcg/kg. In a separate two-year study in male Sprague-Dawley rats, no gliomas were observed at the same oral dose of 50 mcg/kg, although a statistically significant increase in hepatocellular tumors was again noted at this dose. Similar findings were reported with concurrent reference corticosteroids, prednisolone and triamcinolone acetonide. In a 91-week study in mice, budesonide did not demonstrate any treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.1 times the maximum recommended human dose on a body surface area basis).

Budesonide was assessed for genotoxicity and was found to be non-genotoxic in several tests, including the Ames test, the mouse lymphoma cell forward gene mutation (TK +/−) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethality test, the rat hepatocyte UDS test, and the mouse micronucleus test.

Postmarketing Experience

Postmarketing experience has identified cases of Kaposi’s sarcoma in patients receiving corticosteroids for chronic conditions. Patients are advised to inform their healthcare provider if they experience any signs or symptoms indicative of Kaposi’s sarcoma.

Corticosteroid medications, including budesonide delayed-release capsules, are known to suppress the immune system, which may increase the risk of infections caused by viruses, bacteria, fungi, protozoa, or certain parasites. These infections can range from mild to severe and may lead to fatal outcomes. Healthcare providers are recommended to monitor patients closely for signs and symptoms of infection during treatment with budesonide delayed-release capsules. Patients should promptly report any new or worsening signs of infection, including flu-like symptoms such as fever, cough, chills, abdominal pain, fatigue, nausea, vomiting, and diarrhea.

Additionally, there is a risk that inactive (latent) tuberculosis may reactivate in patients taking budesonide delayed-release capsules. Individuals who have not previously contracted chickenpox or measles should avoid contact with those infected with these diseases while on corticosteroid therapy. For patients who are carriers of Hepatitis B Virus (HBV), there is a potential for the virus to reactivate during treatment with budesonide delayed-release capsules. Healthcare providers are advised to conduct HBV testing prior to initiating therapy with budesonide. Furthermore, screening for amebiasis is recommended for individuals who have spent time in tropical regions or present with unexplained diarrhea before starting treatment with budesonide delayed-release capsules.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Patient Information) to understand the medication fully. It is important to inform patients that budesonide delayed-release capsules may lead to hypercorticism and adrenal axis suppression. If patients are transitioning from systemic corticosteroids to budesonide delayed-release capsules, they should follow a taper schedule as instructed by their healthcare provider.

Patients should be made aware that replacing systemic corticosteroids with budesonide delayed-release capsules may unmask previously controlled allergies, such as rhinitis and eczema. Additionally, patients are advised to avoid exposure to individuals with varicella (chicken pox) or measles. They should inform their healthcare provider if they are exposed to these infections or if they develop any new or worsening infections.

It is essential to communicate to patients that Kaposi’s sarcoma has been reported in individuals receiving corticosteroids for chronic conditions. Patients should be instructed to notify their healthcare provider if they experience any signs or symptoms indicative of Kaposi’s sarcoma.

Female patients must be informed that budesonide delayed-release capsules may cause fetal harm. They should notify their healthcare provider if they are known to be pregnant or suspect they may be pregnant.

Patients should take budesonide delayed-release capsules once daily in the morning and swallow the capsules whole without chewing or crushing them. For those who have difficulty swallowing intact capsules, the capsules can be opened and mixed with applesauce. The following steps should be followed:

1. Place one tablespoonful of applesauce into a clean container (e.g., an empty bowl). The applesauce should not be hot and must be soft enough to swallow without chewing.

2. Open the capsule(s).

3. Carefully empty all the granules from the capsule(s) onto the applesauce.

4. Mix the granules with the applesauce.

5. Consume the entire mixture within 30 minutes of preparation, ensuring not to chew or crush the granules. The mixture should not be saved for future use.

6. Follow the applesauce and granules with a glass (8 ounces) of cool water to ensure complete swallowing of the granules.

Lastly, patients should be advised to avoid consuming grapefruit juice during their therapy with budesonide delayed-release capsules.

Storage and Handling

The product is supplied in a container that must be kept tightly closed to maintain its integrity. It should be stored at a temperature of 25°C (77°F), with permissible excursions between 15-30°C (59-86°F) in accordance with USP Controlled Room Temperature guidelines.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)