Budesonide (enteric coated)

Description

Budesonide, the active ingredient in budesonide extended-release capsules (enteric coated), 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, with a molecular weight of 430.5.

Budesonide appears as a white to off-white, tasteless, and 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 × 10³ at ionic strength 0.01.

The budesonide capsules (enteric coated) 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 acetyltributyl citrate, ethylcellulose, hypromellose, methacrylic acid copolymer (type C powder), polyethylene glycol, polysorbate 80, sodium lauryl sulfate, sugar spheres (sucrose and corn starch), talc, and triethyl citrate. The capsule shells consist of gelatin, D&C red #28, D&C red #33, and titanium dioxide. Additionally, the black ink S-1-8114/S-1-8115 contains black iron oxide, D&C yellow #10 aluminum lake, FD&C blue #1 brilliant blue FCF aluminum lake, FD&C blue #2 indigo carmine aluminum lake, FD&C red #40 allura red AC aluminum lake, propylene glycol, and shellac.

Uses and Indications

Budesonide capsules (enteric coated) 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 capsules.

Dosage and Administration

Patients should take the medication once daily in the morning. The capsules must be swallowed whole and should not be chewed or crushed. It is important to avoid the consumption of grapefruit juice during the entire course 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 and weighing more than 25 kg): 9 mg once daily for up to 8 weeks, followed by a reduction to 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 capsules (enteric coated).

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 capsules (enteric coated) is contraindicated in patients with hypersensitivity to any of the ingredients in the formulation. This contraindication is based on the potential for severe allergic reactions, which may pose significant health risks to affected individuals.

Warnings and Precautions

Patients receiving corticosteroids require careful monitoring due to the potential for significant adverse effects.

Hypercorticism and Adrenal Axis Suppression Healthcare professionals should adhere to established warnings regarding corticosteroid use, particularly in pediatric populations and individuals with hepatic impairment, as these groups may be at an elevated risk for hypercorticism and adrenal axis suppression.

Symptoms of Steroid Withdrawal When transitioning patients from other systemic corticosteroids, it is crucial to taper the dosage gradually, especially for those on corticosteroids with high systemic effects. Clinicians should closely monitor for withdrawal symptoms and the potential unmasking of allergies, such as rhinitis and eczema.

Increased Risk of Infection There is an increased risk of infections, including serious and potentially fatal cases of chickenpox and measles. It is essential to monitor patients who have active or quiescent tuberculosis infections, as well as those with untreated fungal, bacterial, systemic viral, or parasitic infections, and ocular herpes simplex.

Other Corticosteroid Effects Patients with concomitant conditions, such as hypertension or diabetes mellitus, should be monitored closely, as corticosteroids may exacerbate these conditions.

In summary, vigilant monitoring and appropriate management strategies are essential to mitigate the risks associated with corticosteroid therapy.

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, particularly in pediatric patients and those with hepatic impairment, who may be at increased risk. It is essential to follow general warnings concerning corticosteroids in these populations. Additionally, patients transitioning from other systemic corticosteroids should be monitored for symptoms of steroid withdrawal, which may include unmasking of allergies such as rhinitis and eczema. A gradual tapering of corticosteroids with high systemic effects is recommended to mitigate these risks.

There is an increased risk of infections, including serious and potentially fatal cases of chickenpox and measles. Patients with active or quiescent tuberculosis, untreated fungal, bacterial, systemic viral, or parasitic infections, or ocular herpes simplex should be closely monitored.

Hypersensitivity reactions to any of the ingredients in budesonide capsules (enteric coated) have been reported. Furthermore, patients with concomitant conditions such as hypertension or diabetes mellitus should be monitored for unwanted effects associated with corticosteroid use.

In rare instances, reports of acute toxicity and/or death following glucocorticoid overdosage have been documented. Management of such cases includes immediate gastric lavage or emesis, followed by supportive and symptomatic therapy. Chronic overdosage may lead to systemic corticosteroid effects, necessitating a temporary reduction in dosage for patients with severe disease requiring continuous steroid therapy.

Animal studies have indicated that single oral doses of 200 and 400 mg/kg were lethal in female and male mice, respectively, with signs of acute toxicity including decreased motor activity, piloerection, and generalized edema.

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 (enteric coated) (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 capsules (enteric coated) 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. The observed safety profile in this population is consistent with that in adults, with no new safety concerns identified.

However, systemic corticosteroids, including budesonide capsules, 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 adults with the same condition.

The safety and effectiveness of budesonide capsules have not been established in pediatric patients under 8 years of age for the treatment of mild to moderate active Crohn's disease. Additionally, the safety and effectiveness for the maintenance of clinical remission in pediatric patients have not been established. An open-label study conducted to evaluate the safety and tolerability of budesonide capsules as maintenance treatment in pediatric patients aged 5 to 17 years did not demonstrate the safety and efficacy for maintaining clinical remission.

Geriatric Use

Clinical studies of budesonide capsules (enteric coated) 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 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 recommended 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 adjust the dosage as necessary to ensure safety and efficacy.

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. In animal reproduction studies, 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 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. It is important to note that all pregnancies carry a background risk of birth defects, loss, or other adverse outcomes.

Some 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. Pregnant women with Crohn's disease 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 an embryo-fetal development study in pregnant rats, doses of budesonide during organogenesis resulted in effects on fetal development and survival at doses up to approximately 500 mcg/kg. Similarly, in pregnant rabbits, doses during the same period led to increased maternal abortion and adverse effects on fetal development at doses up to approximately 25 mcg/kg. Maternal toxicity was noted at lower doses in both species.

In a peri-and post-natal development study, rats dosed with budesonide during the post-coitum period showed no effects on delivery; however, there were significant impacts on the growth and development of offspring, including reduced survival and decreased mean body weights at birth and during lactation, as well as delayed sexual maturation at exposures of 0.2 times the maximum recommended human dose. These findings occurred alongside maternal toxicity.

Healthcare professionals should weigh the potential benefits of budesonide against the risks when considering treatment for pregnant patients.

Lactation

Lactation studies have not been conducted with oral budesonide, including budesonide capsules (enteric coated), 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.

Inhaled budesonide has been associated with undetectable plasma concentrations in breastfed infants, and no adverse events were reported following maternal use. It is important to note that the recommended daily dose of budesonide capsules (enteric coated) is significantly 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 is approximately 5 to 10 nmol/L, which is up to 10 times higher than the 1 to 2 nmol/L observed for the 800 mcg daily dose of inhaled budesonide at steady state.

Given these considerations, the developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for budesonide capsules (enteric coated) and any potential adverse effects on the breastfed infant from the medication or from the underlying maternal condition. Assuming the coefficient of extrapolation between inhaled and oral doses is consistent across all dose levels, budesonide exposure to the nursing child may be up to 10 times higher with therapeutic doses of budesonide capsules compared to inhalation.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available prescribing information. There are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of data when prescribing to this patient population.

Hepatic Impairment

Patients with moderate to severe hepatic impairment (Child-Pugh Class B and C, respectively) may experience an increased risk of hypercorticism and adrenal axis suppression due to heightened systemic exposure to budesonide. Therefore, the use of this medication is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C).

For patients with moderate hepatic impairment (Child-Pugh Class B), it is recommended to monitor for increased signs and/or symptoms of hypercorticism. A dosage reduction should be considered in these patients based on clinical assessment.

In contrast, no dosage adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). Regular monitoring of liver function and clinical response is advised to ensure patient safety and therapeutic efficacy.

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 may lead to systemic effects, including hypercorticism and suppression of the adrenal axis. In cases of chronic overdosage, particularly when necessitated by severe underlying conditions that require ongoing steroid therapy, a temporary reduction in dosage may be warranted 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 models included decreased motor activity, piloerection, and generalized edema. These findings underscore the importance of careful dosing and monitoring in clinical practice to prevent potential overdose scenarios.

Nonclinical Toxicology

Budesonide has been evaluated for its potential teratogenic effects, and no teratogenic effects were identified 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 performed 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 found at the same oral dose of 50 mcg/kg, although a statistically significant increase in hepatocellular tumors was again observed 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 indicated that budesonide capsules (enteric coated) may lead to hypercorticism and adrenal axis suppression. Additionally, the replacement of systemic corticosteroids with budesonide capsules may unmask previously controlled allergies, such as rhinitis and eczema.

There is an observed increased risk of developing various infections, which includes the exacerbation of existing tuberculosis, as well as fungal, bacterial, viral, or parasitic infections, and ocular herpes simplex. Patients are advised to avoid exposure to individuals with chicken pox or measles and to seek immediate consultation with their healthcare provider if such exposure occurs.

Patient Counseling

Patients should be advised 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. If patients are transitioning from systemic corticosteroids to budesonide capsules, they should follow a taper schedule as instructed by their healthcare provider.

Patients should also be made aware that replacing systemic corticosteroids with budesonide capsules may unmask previously controlled allergies, such as rhinitis and eczema. It is crucial to advise patients to avoid exposure to individuals with chicken pox or measles. In the event of exposure, patients should consult their healthcare provider immediately.

Additionally, patients should be informed of their increased risk of developing various infections, including the worsening of existing tuberculosis, and fungal, bacterial, viral, or parasitic infections, as well as ocular herpes simplex. They should be instructed to contact their healthcare provider if they experience any symptoms of infection.

Storage and Handling

The product is supplied in a configuration that includes specific NDC numbers, which are essential for identification and inventory management. It should be stored at a controlled room temperature of 25°C (77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) as outlined by USP guidelines.

To ensure the integrity of the product, it is crucial to keep the container tightly closed at all times. Proper adherence to these storage conditions will help maintain the product's efficacy and safety.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Budesonide (enteric coated) as submitted by Mayne Pharma Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)