Budesonide

Description

Budesonide USP, the active ingredient in 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 exists as a mixture of two epimers (22R and 22S). The molecular formula of budesonide is C25H34O6, with a molecular weight of 430.5.

Budesonide, USP appears as a white to off-white, odorless, 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 5 is 1.6 x 10^3 at ionic strength 0.01.

Each capsule for oral administration contains 3 mg of micronized budesonide, along with inactive ingredients including acetyltributyl citrate, ethylcellulose aqueous dispersion, gelatin, iron oxide red, iron oxide yellow, methacrylic acid copolymer dispersion, polysorbate 80, simethicone emulsion, sodium lauryl sulfate, sugar spheres, talc, titanium dioxide, and triethyl citrate. The capsule shell is printed with black pharmaceutical ink, which consists of iron oxide black, potassium hydroxide, propylene glycol, and shellac.

Uses and Indications

Budesonide delayed-release capsules are 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, this drug is indicated for the 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.

There are no teratogenic or nonteratogenic effects associated with the use of budesonide delayed-release capsules.

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 in patients with mild to moderate Crohn's disease, the following dosages are recommended:

• 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 hepatic impairment, particularly those classified as Child-Pugh Class B (moderate hepatic impairment), 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. Clinicians should remain vigilant for withdrawal symptoms and the potential 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. Notably, there is a risk of potentially fatal infections such as varicella and measles. Continuous monitoring for new or worsening infections is crucial, and healthcare providers should consider discontinuing the drug if such infections arise. The use of this therapy is contraindicated in patients with active 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. Therefore, it is important to monitor for any signs of this condition.

Healthcare professionals should also be aware of the potential effects of corticosteroids on patients with pre-existing conditions, such as hypertension and diabetes mellitus, and monitor these patients accordingly.

Side Effects

Patients receiving treatment may experience a range of adverse reactions. The most common adverse reactions, occurring in 5% or more of participants, 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 symptoms of steroid withdrawal, which may include unmasking of allergies such as rhinitis and eczema.

Immunosuppression is another significant concern, as it increases the risk of various 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. The use of this treatment is contraindicated 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, patients with concomitant conditions such as hypertension or diabetes mellitus should be monitored closely, as corticosteroids may exacerbate these conditions.

Hypersensitivity reactions to budesonide or any of its components have been noted and should be taken into account when prescribing.

In terms of fetal and neonatal safety, hypoadrenalism may occur in infants born to mothers who received corticosteroids during pregnancy. These infants should be carefully observed for signs of hypoadrenalism, which may manifest as poor feeding, irritability, weakness, and vomiting.

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 toxicity 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 indication.

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 and over 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.

Other reported clinical experience has not identified significant differences in responses between elderly patients and younger patients. However, in general, dose selection for geriatric patients should be approached with caution. It is advisable to start at the low end of the dosing range, 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.

Healthcare providers should closely monitor elderly patients for any potential adverse effects and consider individual patient factors when determining the appropriate dosage.

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. Animal reproduction studies have demonstrated that administration of subcutaneous budesonide during organogenesis in pregnant rats and rabbits, at doses approximately 0.5 times and 0.05 times the maximum recommended human dose, respectively, resulted in increased fetal loss, decreased pup weights, and skeletal abnormalities. Maternal toxicity was also observed in both species at these dose levels.

Based on animal data, healthcare professionals should advise pregnant women of the potential risks to a fetus. The estimated background risk of major birth defects and miscarriage in the general U.S. population is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage in the indicated population remains unknown. All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes.

Some published epidemiological studies indicate an association between adverse pregnancy outcomes in women with Crohn's disease, including preterm birth and low birth weight infants, particularly during periods of increased disease activity. Therefore, pregnant women with Crohn's disease should be counseled on the importance of controlling their disease.

Hypoadrenalism may occur in infants born to mothers receiving corticosteroids during pregnancy. Infants should be carefully monitored for signs of hypoadrenalism, which may include poor feeding, irritability, weakness, and vomiting. Budesonide has been shown to be teratogenic and embryolethal in animal studies. In an embryo-fetal development study involving pregnant rats, subcutaneous doses of budesonide during organogenesis resulted in adverse effects on fetal development and survival at doses up to approximately 500 mcg/kg. Similarly, in pregnant rabbits, doses up to approximately 25 mcg/kg led to increased maternal abortion rates and adverse effects on fetal development, including reduced litter weights.

Maternal toxicity, characterized by reduced body weight gain, was noted at subcutaneous doses of 5 mcg/kg in rabbits and 500 mcg/kg in rats. In a peri-and post-natal development study, while budesonide did not affect delivery, it did impact the growth and development of offspring, with reduced offspring survival and decreased mean body weights at birth and during lactation observed at exposures as low as 0.02 times the maximum recommended human dose.

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, with infant doses estimated to be approximately 0.3% to 1% of the maternal weight-adjusted dosage. The milk/plasma ratio for budesonide in this context ranged between 0.4 and 0.5.

No adverse events were noted in breastfed infants following maternal use of inhaled budesonide, and budesonide plasma concentrations were not detected in these infants. 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 medication 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. The maximum plasma concentration of budesonide following a 9 mg daily dose of oral budesonide is approximately 2.15 to 4.31 ng/mL, which is up to 10 times higher than the 0.43 to 0.86 ng/mL observed for the 800 mcg daily dose of inhaled budesonide at steady state. Assuming a constant coefficient of extrapolation between inhaled and oral doses, 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 not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

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 treatment includes gastric lavage or the induction of emesis, followed by supportive and symptomatic care to manage any arising complications.

Prolonged use of corticosteroids at excessive doses can lead to systemic effects, including hypercorticism and suppression of the adrenal axis. In cases of chronic overdosage, particularly when treating severe conditions that necessitate ongoing steroid therapy, it may be appropriate to temporarily reduce the dosage to mitigate adverse effects.

Experimental studies have demonstrated 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. Healthcare professionals should remain vigilant for these symptoms in cases of suspected overdosage and initiate appropriate management strategies promptly.

Nonclinical Toxicology

Budesonide has been evaluated for its nonclinical toxicology profile, including teratogenic and non-teratogenic effects, as well as carcinogenicity and mutagenicity.

No teratogenic effects were observed in the studies conducted. In terms of non-teratogenic effects, budesonide did not impact fertility 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 (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 adverse effects were recorded 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 performed in both rats and mice. A two-year study in Sprague-Dawley rats revealed a statistically significant increase in the incidence of gliomas 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, there were increased incidences of primary hepatocellular tumors 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 observed 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 detected at the same oral dose of 50 mcg/kg, although a statistically significant increase in hepatocellular tumors was noted. The concurrent reference corticosteroids, prednisolone and triamcinolone acetonide, exhibited similar findings. In a 91-week study in mice, budesonide did not demonstrate 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 also 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

Kaposi's sarcoma has been reported in patients receiving corticosteroids for chronic conditions. Patients are advised to inform their healthcare provider if they experience signs or symptoms suggestive of Kaposi's sarcoma.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) thoroughly to understand the medication's use and potential risks. It is important to inform patients that budesonide capsules (enteric coated) may lead to hypercorticism and adrenal axis suppression. Patients should be instructed to follow a taper schedule as directed by their healthcare provider when transitioning from systemic corticosteroids to budesonide capsules (enteric coated).

Providers should also make patients aware that the replacement of systemic corticosteroids with budesonide capsules (enteric coated) may unmask previously controlled allergies, such as rhinitis and eczema. Patients should be cautioned to avoid exposure to individuals with varicella (chicken pox) or measles, as these infections can pose significant risks.

In the event of exposure to varicella or measles, or if patients develop a new or worsening infection, they should be advised to promptly inform their healthcare provider. Additionally, healthcare providers should discuss the potential risk of Kaposi's sarcoma, which has been reported in patients receiving corticosteroids for chronic conditions. Patients should be instructed to report any signs or symptoms indicative of Kaposi's sarcoma to their healthcare provider immediately.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a temperature range of 20°C to 25°C (68°F to 77°F), adhering to the guidelines set forth by the United States Pharmacopeia (USP) for Controlled Room Temperature. It is essential to keep the container tightly closed to maintain the integrity of the product.

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 Major Pharmaceuticals. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)