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. Pediatric use information is approved for Perrigo Pharma International DAC’s ENTOCORT EC (budesonide) capsules. However, due to Perrigo Pharma International DAC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information...
• Take budesonide capsules (enteric coated) once daily in the morning. • Swallow budesonide capsules (enteric coated) whole. Do not chew or crush. • Avoid consumption of grapefruit juice for the duration of budesonide capsules (enteric coated) therapy [see Drug Interactions ( 7.1 )] . The recommended dosage of budesonide capsules (enteric coated) is: Adults 9 mg orally once daily for up to 8 weeks. Repeated 8 week...
Budesonide capsules (enteric coated) 3 mg are hard gelatin capsules with a Swedish orange opaque cap and body containing enteric coated pellets. The cap is imprinted with SC 2091 in black ink. They are supplied as follows: NDC 0781–2072–01 Bottles of 100 capsules NDC 0781–2072–05 Bottles of 500 capsules Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room...
www.fda.gov/medwatchBudesonide capsules (enteric coated) are indicated for the treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon.
Pediatric use information is approved for Perrigo Pharma International DAC’s ENTOCORT EC (budesonide) capsules. However, due to Perrigo Pharma International DAC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
Budesonide capsules (enteric coated) are 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.
The recommended dosage of budesonide capsules (enteric coated) is:
Adults
9 mg orally once daily for up to 8 weeks. Repeated 8 week courses of budesonide capsules (enteric coated) can be given for recurring episodes of active disease.
Pediatric use information is approved for Perrigo Pharma International DAC’s ENTOCORT EC (budesonide) capsules. However, due to Perrigo Pharma International DAC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
The recommended dosage in adults, following an 8 week course(s) of treatment for active disease and once the patient's symptoms are controlled (CDAI less than 150), is budesonide capsules (enteric coated) 6 mg orally once daily for maintenance of clinical remission up to 3 months. If symptom control is still maintained at 3 months an attempt to taper to complete cessation is recommended. Continued treatment with budesonide capsules (enteric coated) 6 mg for more than 3 months has not been shown to provide substantial clinical benefit.
Patients with mild to moderate active Crohn's disease involving the ileum and/or ascending colon have been switched from oral prednisolone to budesonide capsules (enteric coated) with no reported episodes of adrenal insufficiency. Since prednisolone should not be stopped abruptly, tapering should begin concomitantly with initiating budesonide capsules (enteric coated) treatment.
Consider reducing the dosage of budesonide capsules (enteric coated) to 3 mg once daily for adult patients with moderate hepatic impairment (Child-Pugh Class B). Avoid use in patients with severe hepatic impairment (Child-Pugh Class C) [see Warnings and Precautions (5.1), Use in Specific Populations (8.6)].
Capsules: 3 mg are hard gelatin capsules with Swedish orange opaque cap and body, coded with SC 2091on the cap.
Budesonide capsules (enteric coated) are contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of budesonide capsules (enteric coated). Serious hypersensitivity reactions, including anaphylaxis have occurred [see Adverse Reactions (6.2)].
When corticosteroids are used chronically, systemic effects such as hypercorticism and adrenal axis suppression may occur. Corticosteroids can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic corticosteroid is recommended. Since budesonide capsules (enteric coated) contains a corticosteroid, general warnings concerning corticosteroids should be followed [see Warnings and Precautions (5.2), (5.3), (5.4)].
Pediatric patients with Crohn’s disease have a slightly higher systemic exposure of budesonide and increased cortisol suppression than adults with Crohn’s disease [see Use in Specific Populations (8.4), Clinical Pharmacology (12.2)]. Patients with moderate to severe hepatic impairment (Child-Pugh Class B and C respectively) could be at an increased risk of hypercorticism and adrenal axis suppression due to an increased systemic exposure of oral budesonide. Avoid use in patients with severe hepatic impairment (Child-Pugh Class C). Monitor for increased signs and/or symptoms of hypercorticism and consider reducing the dosage in patients with moderate hepatic impairment (Child-Pugh Class B) [see Dosage and Administration (2.4), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
Monitor patients who are transferred from corticosteroid treatment with high systemic effects to corticosteroids with lower systemic availability, such as budesonide capsules (enteric coated), since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal axis suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of corticosteroid treatment with high systemic effects should be reduced cautiously.
Replacement of systemic corticosteroids with budesonide capsules (enteric coated) may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.
Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of corticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure.
How the dose, route and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See prescribing information for VZIG and IG). If chicken pox develops, treatment with antiviral agents may be considered.
Corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections, or ocular herpes simplex.
Monitor patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where corticosteroids may have unwanted effects.
The following clinically significant adverse reactions are described elsewhere in labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adults
The data described below reflect exposure to budesonide capsules (enteric coated) in 520 patients with Crohn's disease, including 520 exposed to 9 mg per day (total daily dose) for 8 weeks and 145 exposed to 6 mg per day for one year in placebo controlled clinical trials. Of the 520 patients, 38% were males and the age range was 17 to 74 years.
Treatment of Mild to Moderate Active Crohn's Disease
The safety of budesonide capsules (enteric coated) was evaluated in 651 adult patients in five clinical trials of 8 weeks duration in patients with active mild to moderate Crohn's disease. The most common adverse reactions, occurring in greater than or equal to 5% of the patients, are listed in Table 1.
Adverse Reaction | Budesonide Capsules (enteric coated) 9 mg n=520 Number (%) | Placebo n=107 Number (%) | Prednisolone† 40 mg n=145 Number (%) | Comparator‡ n=88 Number (%) |
|---|---|---|---|---|
Headache | 107 (21) | 19 (18) | 31 (21) | 11 (13) |
Respiratory Infection | 55 (11) | 7 (7) | 20 (14) | 5 (6) |
Nausea | 57 (11) | 10 (9) | 18 (12) | 7 (8) |
Back Pain | 36 (7) | 10 (9) | 17 (12) | 5 (6) |
Dyspepsia | 31 (6) | 4 (4) | 17 (12) | 3 (3) |
Dizziness | 38 (7) | 5 (5) | 18 (12) | 5 (6) |
Abdominal Pain | 32 (6) | 18 (17) | 6 (4) | 10 (11) |
Flatulence | 30 (6) | 6 (6) | 12 (8) | 5 (6) |
Vomiting | 29 (6) | 6 (6) | 6 (4) | 6 (7) |
Fatigue | 25 (5) | 8 (7) | 11 (8) | 0 (0) |
Pain | 24 (5) | 8 (7) | 17 (12) | 2 (2) |
* Occurring in greater than or equal to 5% of the patients in any treated group.
† Prednisolone tapering scheme: either 40 mg in week 1 to 2, thereafter tapering with 5 mg per week; or 40 mg in week 1to 2, 30 mg in week 3 to 4, thereafter tapering with 5 mg per week.
‡ This drug is not approved for the treatment of Crohn's disease in the United States.
The incidence of signs and symptoms of hypercorticism reported by active questioning of patients in 4 of the 5 short-term clinical trials are displayed in Table 2.
Signs/Symptom | Budesonide Capsules (enteric coated) 9 mg n=427 Number (%) | Placebo n=107 Number (%) | Prednisolone* 40 mg n=145 Number (%) |
|---|---|---|---|
Total | 145 (34%) | 29 (27%) | 69 (48%) |
Acne | 63 (15) | 14 (13) | 33 (23)† |
Bruising Easily | 63 (15) | 12 (11) | 13 (9) |
Moon Face | 46 (11) | 4 (4) | 53 (37) |
Swollen Ankles | 32 (7) | 6 (6) | 13 (9) |
Hirsutism‡ | 22 (5) | 2 (2) | 5 (3) |
Buffalo Hump | 6 (1) | 2 (2) | 5 (3) |
Skin Striae | 4 (1) | 2 (2) | 0 (0) |
* Prednisolone tapering scheme: either 40 mg in week 1 to 2, thereafter tapering with 5 mg/week; or 40 mg in week 1 to 2, 30 mg in week 3 to 4, thereafter tapering with 5 mg/week.
† Statistically significantly different from budesonide capsules (enteric coated) 9 mg.
‡ Including hair growth increased, local and hair growth increased, general.
Maintenance of Clinical Remission of Mild to Moderate Crohn's Disease
The safety of budesonide capsules (enteric coated) was evaluated in 233 adult patients in four long-term clinical trials (52 weeks) of maintenance of clinical remission in patients with mild to moderate Crohn's disease. A total of 145 patients were treated with budesonide capsules (enteric coated) 6 mg once daily.
The adverse reaction profile of budesonide capsules (enteric coated) 6 mg once daily in maintenance of Crohn's disease was similar to that of short-term treatment with budesonide capsules (enteric coated) 9 mg once daily in active Crohn's disease. In the long-term clinical trials, the following adverse reactions occurred in greater than or equal to 5% and are not listed in Table 1: diarrhea (10%); sinusitis (8%); infection viral (6%); and arthralgia (5%).
Signs/symptoms of hypercorticism reported by active questioning of patients in the long-term maintenance clinical trials are displayed in Table 3.
Signs/Symptom | BudesonideCapsules (enteric coated) 3 mg n=88 Number (%) | Budesonide Capsules (enteric coated) 6 mg n=145 Number (%) | Placebo n=143 Number (%) |
|---|---|---|---|
Bruising easily | 4 (5) | 15 (10) | 5 (4) |
Acne | 4 (5) | 14 (10) | 3 (2) |
Moon face | 3 (3) | 6 (4) | 0 |
Hirsutism | 2 (2) | 5 (3) | 1 (1) |
Swollen ankles | 2 (2) | 3 (2) | 3 (2) |
Buffalo hump | 1 (1) | 1 (1) | 0 |
Skin striae | 2 (2) | 0 | 0 |
The incidence of signs/symptoms of hypercorticism as described above in long-term maintenance clinical trials was similar to that seen in the short-term treatment clinical trials.
Less Common Adverse Reactions in Treatment and Maintenance Clinical Trials
Less common adverse reactions (less than 5%), occurring in adult patients treated with budesonide capsules (enteric coated) 9 mg (total daily dose) in short-term treatment clinical studies and/or budesonide capsules (enteric coated) 6 mg (total daily dose) in long-term maintenance clinical trials, with an incidence are listed below by system organ class:
Cardiac disorders: palpitation, tachycardia
Eye disorders: eye abnormality, vision abnormal
General disorders and administration site conditions: asthenia, chest pain, dependent edema, face edema, flu-like disorder, malaise, fever
Gastrointestinal disorders: anus disorder, enteritis, epigastric pain, gastrointestinal fistula, glossitis, hemorrhoids, intestinal obstruction, tongue edema, tooth disorder
Infections and infestations: Ear infection - not otherwise specified, bronchitis, abscess, rhinitis, urinary tract infection, thrush
Investigations: weight increased
Metabolism and nutrition disorders: appetite increased
Musculoskeletal and connective tissue disorders: arthritis, cramps, myalgia
Nervous system disorders: hyperkinesia, parasthesia, tremor, vertigo, somnolence, amnesia
Psychiatric disorders: agitation, confusion, insomnia, nervousness, sleep disorder
Renal and urinary disorders: dysuria, micturition frequency, nocturia
Reproductive system and breast disorders: intermenstrual bleeding, menstrual disorder
Respiratory, thoracic and mediastinal disorders: dyspnea, pharynx disorder
Skin and subcutaneous tissue disorders: alopecia, dermatitis, eczema, skin disorder, sweating increased, purpura
Vascular disorders: flushing, hypertension
Bone Mineral Density
A randomized, open, parallel-group multicenter safety clinical trial specifically compared the effect of budesonide capsules (enteric coated) (less than 9 mg per day) and prednisolone (less than 40 mg per day) on bone mineral density over 2 years when used at doses adjusted to disease severity. Bone mineral density decreased significantly less with budesonide capsules (enteric coated) than with prednisolone in steroid-naïve patients, whereas no difference could be detected between treatment groups for steroid-dependent patients and previous steroid users. The incidence of symptoms associated with hypercorticism was significantly higher with prednisolone treatment.
Clinical Laboratory Test Findings
The following potentially clinically significant laboratory changes in clinical trials, irrespective of relationship to budesonide capsules (enteric coated), were reported in greater than or equal to 1% of patients: hypokalemia, leukocytosis, anemia, hematuria, pyuria, erythrocyte sedimentation rate increased, alkaline phosphatase increased, atypical neutrophils, c-reactive protein increased and adrenal insufficiency.
Pediatric use information is approved for Perrigo Pharma International DAC’s ENTOCORT EC (budesonide) capsules. However, due to Perrigo Pharma International DAC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
The following adverse reactions have been reported during post-approval use of budesonide capsules (enteric coated). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Immune System Disorders: Anaphylactic reactions
Nervous System Disorders: Benign intracranial hypertension
Psychiatric Disorders: Mood swings
Budesonide is a substrate for CYP3A4. Avoid use with CYP3A4 inhibitors. Concomitant oral administration of a strong CYP3A4 inhibitor (ketoconazole) caused an eight-fold increase of the systemic exposure to oral budesonide. Inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, and cyclosporine) can increase systemic budesonide concentrations [see Clinical Pharmacology (12.3)].
Grapefruit Juice
Avoid ingestion of grapefruit juice with budesonide. Intake of grapefruit juice which inhibits CYP3A4 activity with budesonide can increase the systemic exposure for budesonide [see Clinical Pharmacology (12.3)].
Risk Summary
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. There are clinical considerations [see Clinical Considerations]. In animal reproduction studies with pregnant rats and rabbits, administration of subcutaneous budesonide during organogenesis at doses approximately 0.5 times or 0.05 times, respectively, the maximum recommended human dose, resulted in increased fetal loss, decreased pup weights, and skeletal abnormalities. Maternal toxicity was observed in both rats and rabbits at these dose levels [see Data ]. Based on animal data, advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage of the indicated population is unknown. 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.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Some published epidemiological studies show an association of adverse pregnancy outcomes in women with Crohn's disease, including preterm birth and low birth weight infants, during periods of increased disease activity (including increased stool frequency and abdominal pain). Pregnant women with Crohn's disease should be counseled regarding the importance of controlling disease.
Fetal/Neonatal Adverse Reactions
Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Infants should be carefully observed for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting, and managed accordingly [see Warnings and Precautions (5.1)].
Data
Animal Data
Budesonide was teratogenic and embryolethal in rabbits and rats.
In an embryo-fetal development study in pregnant rats dosed subcutaneously with budesonide during the period of organogenesis from gestation days 6 to 17 there was a prolonged duration of pregnancy in dams and effects on fetal development and survival at subcutaneous doses up to approximately 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 7 to 20, increase in maternal abortion, and effects on fetal development and reduction in litter weights at subcutaneous doses up to approximately 25 mcg/kg in rabbits (approximately 0.05 times the maximum recommended human dose on a body surface area basis). Maternal toxicity, including reduction in body weight gain, was observed at subcutaneous doses of 5 mcg/kg in rabbits (approximately 0.01 times the maximum recommended human dose on a body surface area basis) and 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis).
In a peri- and post-natal development study, rats dosed subcutaneously with budesonide during the period of Day 15 post coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect on growth and development of offspring. In addition, offspring survival was reduced and surviving offspring had decreased mean body weights at birth and during lactation along with delayed sexual maturation at exposures ≥0.5 times the MRHD (on a mg/m2 basis at maternal subcutaneous doses of 500 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity.
Risk Summary
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 the effects of the drug on milk production. One published study reports that budesonide is present in human milk following maternal inhalation of budesonide [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for budesonide capsules (enteric coated) and any potential adverse effects on the breastfed infant from budesonide capsules (enteric coated), or from the underlying maternal condition.
Data
One published study reports that budesonide is present in human milk following maternal inhalation of budesonide which resulted in infant doses approximately 0.3% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.4 and 0.5. Budesonide plasma concentrations were not detected and no adverse events were noted in the breastfed infants following maternal use of inhaled budesonide. The recommended daily dose of budesonide capsules (enteric coated) is higher (up to 9 mg daily) compared with inhaled budesonide (up to 800 mcg daily) given to mothers in the above described study. The maximum budesonide plasma concentration following a 9 mg daily dose (in both single- and repeated-dose pharmacokinetic studies) of oral budesonide is approximately 5 to 10 nmol/L which is up to 10 times higher than the 1 to 2 nmol/L for a 800 mcg daily dose of inhaled budesonide at steady state in the above inhalation study. Assuming the coefficient of extrapolation between the inhaled and oral doses is constant across all dose levels, at therapeutic doses of budesonide capsules (enteric coated), budesonide exposure to the nursing child may be up to 10 times higher than that by budesonide inhalation.
Systemic corticosteroids, including budesonide capsules (enteric coated), may cause a reduction of growth velocity in pediatric patients. Pediatric patients with Crohn's disease have a 17% higher mean systemic exposure and cortisol suppression than adults with Crohn's disease [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)].
The safety and effectiveness of budesonide capsules (enteric coated) have not been established in pediatric patients less than 8 years of age.
Pediatric use information is approved for Perrigo Pharma International DAC’s ENTOCORT EC (budesonide) capsules. Additional information describing a clinical study in which efficacy was not demonstrated in patients ages 5 to 17 years for another indication is approved for Perrigo Pharma International DAC’s ENTOCORT EC (budesonide) capsules. However, due to Perrigo Pharma International DAC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
Clinical studies of budesonide capsules (enteric coated) did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of the 651 patients treated with budesonide capsules (enteric coated) in clinical studies, 17 (3%) were greater than or equal to 65 years of age and none were greater than 74 years of age. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Patients with moderate to severe hepatic impairment (Child-Pugh Class B and C, respectively) could be at an increased risk of hypercorticism and adrenal axis suppression due to an increased systemic exposure to budesonide [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. Avoid use in patients with severe hepatic impairment (Child-Pugh Class C). Monitor for increased signs and/or symptoms of hypercorticism and consider dosage reduction in patients with moderate hepatic impairment (Child-Pugh Class B) [see Dosage and Administration (2.4)]. No dosage adjustment is needed in patients with mild hepatic impairment (Child-Pugh Class A).
Reports of acute toxicity and/or death following overdosage of glucocorticoids are rare. Treatment consists of immediate gastric lavage or emesis followed by supportive and symptomatic therapy.
If corticosteroids are used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism and adrenal axis suppression may occur. For chronic overdosage in the case of severe disease requiring continuous steroid therapy, the dosage may be reduced temporarily.
Single oral doses of 200 and 400 mg/kg were lethal in female and male mice, respectively. The signs of acute toxicity were decreased motor activity, piloerection and generalized edema.
Budesonide, the active ingredient of budesonide capsules (enteric coated), is a synthetic corticosteroid. Budesonide is designated chemically as (RS)-11β, 16α, 17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide is provided as a mixture of two epimers (22R and 22S). The molecular formula of budesonide is C25H34O6 and its molecular weight is 430.5. Its structural formula is:
Budesonide is a white or almost white crystalline, odorless powder that is practically insoluble in water, freely soluble in dichloromethane and sparingly soluble in alcohol. Its partition coefficient between octanol and water at pH 5 is 1.6 × 103 ionic strength 0.01.
Budesonide capsules (enteric coated) is formulated as hard gelatin capsules filled with enteric-coated pellets that dissolve at pH greater than 5.5. Each capsule for oral administration contains 3 mg of micronized budesonide with the following inactive ingredients: acetyl tributyl citrate, cetyl alcohol, ethylcellulose, methacrylic acid/ethyl acrylate copolymer, polysorbate 80, sodium lauryl sulfate, sugar spheres comprised of sucrose and starch, talc, and triethyl citrate. The capsule shells have the following inactive ingredients: FD&C Blue No.1, FD&C Red No.40, gelatin, and titanium dioxide. The imprinting ink contains the following: black iron oxide, potassium hydroxide, propylene glycol, shellac, strong ammonia solution.
Budesonide is an anti-inflammatory corticosteroid and has a high glucocorticoid effect and a weak mineralocorticoid effect, and the affinity of budesonide to glucocorticoid receptors, which reflects the intrinsic potency of the drug, is about 200-fold that of cortisol and 15-fold that of prednisolone.
Treatment with glucocorticoids, including budesonide capsules (enteric coated) is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function. There was a positive correlation between the percent (%) reduction of AUC0-24 of plasma cortisol and systemic exposure to budesonide both in pediatric and adult patients.
Adults
Plasma cortisol suppression was compared following five days' administration of budesonide capsules (enteric coated) and prednisolone in a crossover study in healthy volunteers. The mean decrease in the area under the plasma cortisol concentration-time curve over 24 hour (AUC0-24) was greater (78%) with prednisolone 20 mg per day compared to 45% with budesonide capsules (enteric coated) 9 mg per day.
Pediatric use information is approved for Perrigo Pharma International DAC’s ENTOCORT EC (budesonide) capsules. However, due to Perrigo Pharma International DAC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
Absorption
Following administration of budesonide capsules (enteric coated), the time to peak concentration varied in individual patients between 30 and 600 minutes. Mean oral bioavailability of budesonide ranged from 9% to 21% both in patients and in healthy subjects, demonstrating a high first-pass elimination of the drug.
Budesonide pharmacokinetics were dose-proportional following repeated administration in the dose range of 3 to 15 mg. No accumulation of budesonide was observed following repeated dosing.
Following oral administration of 9 mg budesonide capsules (enteric coated) for five days in healthy subjects, the mean peak plasma concentration and the steady state area under the plasma concentration time curve for budesonide were 5.3 ± 1.8 nmol/L and 37 ±14.6 nmol•hr/L, respectively.
Following administration of 9 mg budesonide capsules (enteric coated) once daily in patients with active Crohn's disease, the mean peak plasma concentration and AUC were 4 ±2.1 nmol/L and 35 ±19.8 nmol•h/L, respectively.
Concomitant administration of a high-fat meal delayed the time to peak concentration of budesonide from budesonide capsules (enteric coated) by 2.3 hours but did not significantly affect the AUC in healthy subjects.
Distribution
The mean volume of distribution (Vss) of budesonide varied between 2.2 and 3.9 L/kg in healthy subjects and in patients. Plasma protein binding was estimated to be 85% to 90% in the concentration range 1 to 230 nmol/L, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations was about 0.8.
Elimination
Budesonide had a plasma clearance, 0.9 to 1.8 L/min in healthy adults. Mean plasma clearance after intravenous administration of budesonide in patients with Crohn's disease was 1.0 L/min. These plasma clearance values approached the estimated liver blood flow, and, accordingly, suggest that budesonide is a high hepatic clearance drug. The plasma elimination half-life, after administration of intravenous doses ranged between 2 and 3.6 hours, and did not differ between healthy adults and patients with Crohn's disease.
Metabolism
Following absorption, budesonide is subject to high first pass metabolism (80% to 90%). In vitro experiments in human liver microsomes demonstrated that budesonide is rapidly and extensively biotransformed, mainly by CYP3A4, to its 2 major metabolites, 6β-hydroxy budesonide and 16α-hydroxy prednisolone. The corticosteroid activity of these metabolites was negligible (less than 1/100) in relation to that of the parent compound. In vivo investigations with intravenous doses in healthy subjects were in agreement with the in vitro findings.
Excretion
Budesonide was excreted in urine and feces in the form of metabolites. After oral as well as intravenous administration of micronized [3H]-budesonide, approximately 60% of the recovered radioactivity was found in urine. The major metabolites, including 6β-hydroxy budesonide and 16α-hydroxy prednisolone, are mainly renally excreted, intact or in conjugated forms. No unchanged budesonide was detected in urine.
Specific Populations
Pediatric use information is approved for Perrigo Pharma International DAC’s ENTOCORT EC (budesonide) capsules. However, due to Perrigo Pharma International DAC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
Hepatic Impairment
In patients with mild (Child-Pugh Class A, n=4) or moderate (Child-Pugh Class B, n=4) hepatic impairment, budesonide 4 mg was administered orally as a single dose. The patients with moderate hepatic impairment had a 3.5-fold higher AUC compared to the healthy subjects with normal hepatic function while the patients with mild hepatic impairment had an approximately 1.4-fold higher AUC. The Cmax values demonstrated similar increases [see Dosage and Administration (2.4), Warnings and Precautions (5.1)]. The increased systemic exposure in patients with mild hepatic impairment was not considered to be clinically relevant. Patients with severe liver impairment (Child-Pugh Class C) were not studied.
Drug Interaction Studies
Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase the plasma concentrations of budesonide several-fold. Conversely, induction of CYP3A4 potentially could result in the lowering of budesonide plasma concentrations.
Effects of Other Drugs on Budesonide
Ketoconazole
In an open, non-randomized, cross-over study, 6 healthy subjects were given budesonide 10 mg as a single dose, either alone or concomitantly with the last ketoconazole dose of 3 days treatment with ketoconazole 100 mg twice daily. Co-administration of ketoconazole resulted in an eight-fold increase in AUC of budesonide, compared to budesonide alone [see Drug Interactions (7.1)].
Grapefruit Juice
In an open, randomized, cross-over study, 8 healthy subjects were given budesonide capsules (enteric coated) 3 mg, either alone, or concomitantly with 600 mL concentrated grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), on the last of 4 daily administrations. Concomitant administration of grapefruit juice resulted in a 2-fold increase of the bioavailability of budesonide compared to budesonide alone [see Drug Interactions (7.1)].
Oral Contraceptives (CYP3A4 Substrates)
In a parallel study, the pharmacokinetics of budesonide were not significantly different between healthy female subjects who received oral contraceptives containing desogestrel 0.15 mg and ethinyl estradiol 30 mcg and healthy female subjects who did not receive oral contraceptives. Budesonide 4.5 mg once daily (one-half the recommended dose) for one week did not affect the plasma concentrations of ethinyl estradiol, a CYP3A4 substrate. The effect of budesonide 9 mg once daily on the plasma concentrations of ethinyl estradiol was not studied.
Omeprazole
In a study in 11 healthy subjects, performed in a double-blind, randomized, placebo controlled manner, the effect of 5 to 6 days treatment with omeprazole 20 mg once daily on the pharmacokinetics of budesonide administered as budesonide capsules (enteric coated) 9 mg as a single dose was investigated. Omeprazole 20 mg once daily did not affect the absorption or pharmacokinetics of budesonide.
Cimetidine
In an open, non-randomized, cross-over study, the potential effect of cimetidine on the pharmacokinetics of budesonide was studied. Six healthy subjects received cimetidine 1 gram daily (200 mg with meals and 400 mg at night) for 2 separate 3-day periods. Budesonide 4 mg was administered either alone or on the last day of one of the cimetidine treatment periods. Co-administration of cimetidine resulted in a 52% and 31% increase in the budesonide peak plasma concentration and the AUC of budesonide, respectively.
Carcinogenicity studies with budesonide were conducted in rats and mice. In a two-year study in Sprague-Dawley rats, budesonide caused 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). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.023 times the maximum recommended human dose on a body surface area basis) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In an additional two-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no 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 not genotoxic in 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.
In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.07 times the maximum recommended human dose on a body surface area basis). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.02 times the maximum recommended human dose on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately 0.005 times the maximum recommended human dose on a body surface area basis).
Adults
The efficacy of budesonide capsules (enteric coated) were evaluated in 994 patients with mild to moderate active Crohn's disease of the ileum and/or ascending colon in 5 randomized and double-blind studies of 8 weeks duration. The study patients ranged in age from 17 to 85 (mean 35), 40% were male and 97% were white. The Crohn's Disease Activity Index (CDAI) was the main clinical assessment used for determining efficacy in these 5 studies.1 The CDAI is a validated index based on subjective aspects rated by the patient (frequency of liquid or very soft stools, abdominal pain rating and general well-being) and objective observations (number of extraintestinal symptoms, need for antidiarrheal drugs, presence of abdominal mass, body weight and hematocrit). Clinical improvement, defined as a CDAI score of less than or equal to 150 assessed after 8 weeks of treatment, was the primary efficacy variable in these 5 comparative efficacy studies of budesonide capsules (enteric coated). Safety assessments in these studies included monitoring of adverse reactions. A checklist of potential symptoms of hypercorticism was used.
One study (Study 1) compared the efficacy of budesonide capsules (enteric coated) 9 mg daily in the morning to a comparator. At baseline, the median CDAI was 272. Budesonide capsules (enteric coated) 9 mg daily resulted in a significantly higher clinical improvement rate at Week 8 than the comparator. See Table 5.
| Clinical Study | BudesonideCapsules (enteric coated) 9 mg Daily | Budesonide Capsules (enteric coated) 4.5 mg Twice Daily | Comparator* | Placebo | Prednisolone |
|---|---|---|---|---|---|
1 | 62/91 (69%)† | 37/83 (45%) | |||
2 | 31/61 (51%)‡ | 13/64 (20%) | |||
3 | 38/79 (48%) | 41/78 (53%) | 13/40 (33%) | ||
4 | 35/58 (60%) | 25/60 (42%) | 35/58 (60%) | ||
5 | 45/86 (52%) | 56/85 (65%) |
* This drug is not approved for the treatment of Crohn's disease in the United States.
† p=0.0004 compared to comparator.
‡ p=0.001 compared to placebo.
Two placebo-controlled clinical trials (Studies 2 and 3) were conducted. Study 2 involved 258 patients and tested the effects of graded doses of budesonide capsules (enteric coated) (1.5 mg twice daily, 4.5 mg twice daily, or 7.5 mg twice daily) versus placebo. At baseline, the median CDAI was 290. The 1.5 mg twice daily arm (data not shown) could not be differentiated from placebo. The 4.5 mg twice daily arm was statistically different from placebo (Table 5), while no additional benefit was seen when the daily budesonide capsules (enteric coated) dose was increased to 15 mg per day (data not shown). Study 3 was a 3-armed parallel group study. The groups were treated with budesonide capsules (enteric coated) 9 mg once daily, budesonide capsules (enteric coated) 4.5 mg twice daily and placebo for 8 weeks, followed by a 2-week double-blind taper phase. The median CDAI at baseline was 263. Neither 9 mg daily nor 4.5 mg twice daily budesonide capsules (enteric coated) dose levels were statistically different from placebo (Table 5). The recommended dosage of budesonide capsules (enteric coated) for the treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon in adults is 9 mg once daily in the morning for up to 8 weeks [see Dosage and Administration (2.1)].
Two clinical trials (Studies 4 and 5) compared budesonide capsules (enteric coated) with oral prednisolone (initial dose 40 mg per day). Study 4 was a 3-armed parallel group study. The groups were treated with budesonide capsules (enteric coated) 9 mg once daily, budesonide capsules (enteric coated) 4.5 mg twice daily and prednisolone 40 mg (tapered dose) for 8 weeks, followed by a 4-week double blind taper phase. At baseline, the median CDAI was 277. Equal clinical improvement rates (60%) were seen in the budesonide capsules (enteric coated) 9 mg daily and the prednisolone groups in Study 4. In Study 5, 13% fewer patients in the budesonide capsules (enteric coated) group experienced clinical improvement than in the prednisolone group (no statistical difference) (Table 5).
The proportion of patients with normal plasma cortisol values (greater than 150 nmol/L) was significantly higher in the budesonide capsules (enteric coated) groups in both trials (60% to 66%) than in the prednisolone groups (26% to 28%) at Week 8.
Pediatric use information is approved for Perrigo Pharma International DAC’s ENTOCORT EC (budesonide) capsules. However, due to Perrigo Pharma International DAC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
Adults
The efficacy of budesonide capsules (enteric coated) for maintenance of clinical remission were evaluated in four double-blind, placebo-controlled, 12-month trials in which 380 patients were randomized and treated once daily with 3 mg or 6 mg budesonide capsules (enteric coated) or placebo. Patients ranged in age from 18 to 73 (mean 37) years. Sixty percent of the patients were female and 99% were Caucasian. The mean CDAI at entry was 96. Among the four clinical trials, approximately 75% of the patients enrolled had exclusively ileal disease. Colonoscopy was not performed following treatment. Budesonide capsules (enteric coated) 6 mg per day prolonged the time to relapse, defined as an increase in CDAI of at least 60 units to a total score greater than 150 or withdrawal due to disease deterioration. The median time to relapse in the pooled population of the 4 studies was 154 days for patients taking placebo, and 268 days for patients taking budesonide capsules (enteric coated) 6 mg per day. Budesonide capsules (enteric coated) 6 mg per day reduced the proportion of patients with loss of symptom control relative to placebo in the pooled population for the 4 studies at 3 months (28% versus 45% for placebo).
Budesonide capsules (enteric coated) 3 mg are hard gelatin capsules with a Swedish orange opaque cap and body containing enteric coated pellets. The cap is imprinted with SC 2091 in black ink. They are supplied as follows:
NDC 0781–2072–01 Bottles of 100 capsules
NDC 0781–2072–05 Bottles of 500 capsules
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Keep container tightly closed.
Advise Patients to read the FDA-Approved patient labeling (Patient Information).
Hypercorticism and Adrenal Axis Suppression
Advise patients that budesonide capsules (enteric coated) may cause hypercorticism and adrenal axis suppression and to follow a taper schedule, as instructed by their healthcare provider if transferring to budesonide capsules (enteric coated) from systemic corticosteroids [see Warnings and Precautions (5.1), (5.2)]. Advise patients that replacement of systemic corticosteroids with budesonide capsules (enteric coated) may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.
Increased Risk of Infection
Advise patients to avoid exposure to people with chicken pox or measles and, if exposed, to consult their healthcare provider immediately. Inform patients that they are at increased risk of developing a variety of infections; including worsening of existing tuberculosis, fungal, bacterial, viral or parasitic infections or ocular herpes simplex and to contact their healthcare provider if they develop any symptoms of infection [see Warnings and Precautions (5.3)].
Pregnancy
Advise female patients that budesonide capsules (enteric coated) may cause fetal harm and to inform their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations (8.1)].
Administration
Advise patients to:
Manufactured by Catalent Pharma Solutions, Somerset, NJ 08873
for Sciecure Pharma Inc., Monmouth Junction, NJ 08852.
Distributed by Sandoz Inc., Princeton, NJ 08540
Rev. October 2017
PATIENT INFORMATION (byoo-DES-oh-nide) | ||
Read this Patient Information before you start taking budesonide capsules (enteric coated) and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. | ||
What are budesonide capsules (enteric coated)?
It is not known if budesonide capsules (enteric coated) are safe and effective in children under 8 years of age. Pediatric use information is approved for Perrigo Pharma International DAC’s ENTOCORT EC (budesonide) capsules. However, due to Perrigo Pharma International DAC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. | ||
Who should not take budesonide capsules (enteric coated)?
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What should I tell my healthcare provider before taking budesonide capsules (enteric coated)?
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Budesonide capsules (enteric coated) and other medicines may affect each other causing side effects. | ||
How should I take budesonide capsules (enteric coated)?
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What should I avoid while taking budesonide capsules (enteric coated)?
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What are the possible side effects of budesonide capsules (enteric coated)?
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The most common side effects of budesonide capsules (enteric coated) in adults include: | ||
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Tell your healthcare provider if you have any side effect that bothers you or that does not go away. | ||
How should I store budesonide capsules (enteric coated)?
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Keep budesonide capsules (enteric coated) and all medicines out of the reach of children. | ||
General information about the safe and effective use of budesonide capsules (enteric coated) | ||
What are the ingredients in budesonide capsules (enteric coated)? Pediatric use information is approved for Perrigo Pharma International DAC’s ENTOCORT EC (budesonide) capsules. However, due to Perrigo Pharma International DAC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. The brands listed are the registered trademarks of their respective owners and are not trademarks of Sandoz Inc. This Patient Information has been approved by the U.S. Food and Drug Administration. Manufactured by Catalent Pharma Solutions, Somerset, NJ 08873 for Sciecure Pharma Inc., Monmouth Junction, NJ 08852. Distributed by Sandoz Inc., Princeton, NJ 08540 Rev. October 2017 | ||
NDC 0781-2072-01
Budesonide Capsules (Enteric Coated)
3 mg
Rx only
100 Capsules
SANDOZ
Every source-derived product name is available through these pages.
| Product NDC | Package NDC |
|---|---|
| 0781-2072 | 0781-2072-01, 0781-2072-05 |
Every source-derived ingredient row is available through these pages.
OpenFDA label data provides additional search and identifier links. DailyMed’s Structured Product Label is the canonical label on FDA.report. Matching records are deduplicated before they are shown below.
| Brand | Generic | Manufacturer | SPL set ID | Effective date | Available safety fields | Join |
|---|---|---|---|---|---|---|
| d303b92d-bd70-4722-9238-695bebe26693 | 95b6b7a2-50f8-40c7-a683-b7eaf78efb34 | 2026-01-08 | Warnings, Adverse reactions | 95b6b7a2-50f8-40c7-a683-b7eaf78efb34 |
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