Budesonide

Description

Budesonide USP, the active ingredient in budesonide delayed-release capsules, is a synthetic corticosteroid. Chemically, it is 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 empirical formula is C25H34O6, with a molecular weight of 430.5.

Budesonide appears as a white to off-white, tasteless, and odorless powder. It is practically insoluble in water and heptane, sparingly soluble in ethanol, and freely soluble in chloroform. The partition coefficient between octanol and water at pH 5 is 1.6 x 10^3 at an ionic strength of 0.01.

Each delayed-release capsule for oral administration contains 3 mg of micronized budesonide, USP, along with inactive ingredients including cetyl alcohol, corn starch, ethyl cellulose, hypromellose, macrogol, methacrylic acid copolymer type C, sodium lauryl sulfate, sugar, talc, and triethyl citrate. The capsule shells consist of D&C yellow #10, FD&C blue #1, FD&C red #40, FD&C yellow #6, gelatin, and titanium dioxide. The monogramming ink contains D&C yellow #10, ethanol, FD&C blue #1, FD&C blue #2, FD&C red #40, iron oxide black, methanol, N-butyl alcohol, 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 of 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 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 components of 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 with treatment. Healthcare professionals should 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. Close monitoring for withdrawal symptoms is necessary, as well as vigilance 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. The use of corticosteroids 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 therapy.

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 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 populations and those with hepatic impairment, who may be at increased risk.

Patients transitioning from other systemic corticosteroids may experience symptoms of steroid withdrawal. It is recommended to taper slowly from corticosteroids with high systemic effects and to monitor for withdrawal symptoms as well as the unmasking of allergies, such as rhinitis and eczema.

Immunosuppression is another significant concern, as treatment may increase 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 drug discontinuation in such cases. The use of this treatment is contraindicated in patients with active fungal infections, Strongyloides infestation, cerebral malaria, and ocular herpes simplex. Additionally, screening for hepatitis B infection is advised.

Kaposi’s sarcoma has been reported in patients receiving corticosteroid therapy, particularly those treated for chronic conditions. Other corticosteroid effects may necessitate monitoring in patients with concomitant conditions, such as hypertension and diabetes mellitus.

Lastly, hypersensitivity reactions to budesonide or any of the ingredients in budesonide delayed-release capsules have been noted and should be taken into account when assessing patient safety.

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 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 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, the safety and effectiveness of budesonide have not been established in pediatric patients under 8 years of age for the treatment of mild to moderate active Crohn’s disease. Additionally, its safety and effectiveness for the maintenance of clinical remission in pediatric patients have not been established. An open-label study 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, 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 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 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 their younger counterparts. 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 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. 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, respectively, the maximum recommended human dose 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 unknown; however, it is acknowledged that all pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. Specifically, 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 have shown 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.

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 the period of organogenesis resulted in effects on fetal development and survival. Similarly, in pregnant rabbits, there was an increase in maternal abortion and adverse effects on fetal development at lower doses.

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. Given these considerations, the use of budesonide during pregnancy should be approached with caution, weighing the potential benefits against the risks.

Lactation

Lactation studies have not been conducted with oral budesonide, and no information is available on the effects of the drug on breastfed infants 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.

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 and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.

The recommended daily dose of oral budesonide 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 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 an 800 mcg daily dose of inhaled budesonide at steady-state. Assuming a constant coefficient of extrapolation between inhaled and oral doses, exposure to budesonide in nursing children at therapeutic doses may be up to 10 times higher than that from 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 hepatic impairment may experience adverse effects during treatment. It is essential to monitor these individuals closely for signs and symptoms of liver dysfunction. Special attention should be given to pediatric patients and those with compromised liver function, as they may be at an increased risk for complications. Regular assessment of liver function is recommended to ensure patient safety and to guide any necessary adjustments in therapy.

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 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

No specific postmarketing experience details are available in the extracted data. As such, there are no additional adverse events or rare case reports to summarize.

Patient Counseling

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

Patients should also be made aware that replacing systemic corticosteroids with budesonide may unmask previously controlled allergies, such as rhinitis and eczema. Therefore, they should monitor for any resurgence of these conditions.

Additionally, patients should be cautioned to avoid exposure to individuals with varicella (chicken pox) or measles. They must inform their healthcare provider if they have been exposed to these infections or if they develop any new or worsening infections.

Lastly, patients should be made aware that Kaposi’s sarcoma has been reported in individuals receiving corticosteroids for chronic conditions. They should promptly inform their healthcare provider if they experience any signs or symptoms indicative of Kaposi’s sarcoma.

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 temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) in accordance with USP Controlled Room Temperature 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 and handling 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 as submitted by Amneal Pharmaceuticals LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)