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 10³ 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 medication 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 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. Following this, the patient should drink 8 ounces of water. 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) 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 tapering 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 to mitigate the risk of steroid withdrawal symptoms. 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 discontinuation of 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.

Routine screening for hepatitis B infection is advised to ensure patient safety during 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 important 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 who are transferred from other systemic corticosteroids may experience symptoms of steroid withdrawal. It is recommended to taper these patients slowly from corticosteroids with high systemic effects and to monitor for withdrawal symptoms and the 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 advised.

Karposi's sarcoma has been reported in patients receiving corticosteroid therapy, particularly those being treated for chronic conditions. Furthermore, patients with concomitant conditions, such as hypertension or diabetes mellitus, should be monitored closely for unwanted effects associated with corticosteroid use.

Hypersensitivity reactions to budesonide or any of its ingredients in delayed-release capsules have been noted.

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 include poor feeding, irritability, weakness, and vomiting.

Drug Interactions

CYP3A4 inhibitors, such as ketoconazole and grapefruit juice, may significantly elevate systemic concentrations of budesonide. Co-administration of these agents is not recommended due to the potential for increased risk of adverse effects 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 systemic 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 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 efficacy and safety is essential in this population to ensure optimal therapeutic outcomes.

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 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, it is acknowledged that 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 have indicated 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 management.

Infants born to mothers receiving corticosteroids during pregnancy may experience hypoadrenalism. It is essential to carefully observe these infants for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting, and to manage them 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 in the presence of maternal toxicity.

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 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. 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

There is no specific information regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

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 treatment 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 potential teratogenic effects, and no teratogenic effects were explicitly identified in the studies conducted.

In terms of non-teratogenic effects, studies in rats indicated that budesonide did not adversely 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 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; however, a statistically significant increase in hepatocellular tumors was again observed. 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

No specific postmarketing experience details have been reported. As such, there are no additional adverse events or rare case reports to summarize at this time.

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 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. 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, 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.

Storage and Handling

The product is supplied in a configuration that includes specific NDC numbers, which are essential for identification and inventory management. It is recommended to store the product at a temperature range of 20°C to 25°C (68°F to 77°F), in accordance with USP Controlled Room Temperature guidelines.

To ensure the integrity of the product, the container must be kept tightly closed at all times. Proper adherence to these storage conditions is crucial for maintaining the quality and efficacy 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 Zydus Pharmaceuticals USA Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)