1.1 Mild to Moderate Active Crohn’s Disease

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.

1.2 Maintenance of Clinical Remission of Mild to Moderate Crohn’s Disease

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.

2.1 Mild to Moderate Active Crohn’s Disease

The recommended adult dosage for the treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon is 9 mg orally taken once daily in the morning for up to 8 weeks. Repeated 8 week courses of budesonide capsules (enteric coated) can be given for recurring episodes of active disease.

2.2 Maintenance of Clinical Remission of Mild to Moderate Crohn’s Disease

Following an 8 week course(s) of treatment for active disease and once the patient’s symptoms are controlled (CDAI less than 150), budesonide capsules (enteric coated) 6 mg orally is recommended 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 capsule (enteric coated) treatment.

2.3 CYP3A4 inhibitors

If concomitant administration with ketoconazole, or any other CYP3A4 inhibitor, is indicated, patients should be closely monitored for increased signs and/or symptoms of hypercorticism. Grapefruit juice, which is known to inhibit CYP3A4, should also be avoided when taking budesonide capsules (enteric coated). In these cases, reduction in the dose of budesonide capsules (enteric coated) should be considered [ ]. see and Drug Interactions (7)Clinical Pharmacology (12.3)

5.1 Hypercorticism and Adrenal Suppression

When glucocorticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Glucocorticosteroids 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 glucocorticosteroid is recommended. Since budesonide capsules (enteric coated) are a glucocorticosteroid, general warnings concerning glucocorticoids should be followed.

5.2 Transferring Patients from Systemic Glucocorticosteroid Therapy

Care is needed in patients who are transferred from glucocorticosteroid 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 suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously.

5.3 Immunosuppression

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 glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure.

How the dose, route and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid 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.

Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections.

Replacement of systemic glucocorticosteroids with budesonide capsules (enteric coated) may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.

5.4 Increased Systemic Glucocorticosteroid Susceptibility

Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis [ ]. see Use in Specific Populations (8.6)

5.5 Other Glucocorticosteroid Effects

Caution should be taken in 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 glucocorticosteroids may have unwanted effects.

6.1 Clinical Trials Experience

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.

The safety of budesonide capsules (enteric coated) was evaluated in 651 patients in five short-term, active disease state studies. They ranged in age from 17 to 74 (mean 35), 40% were male and 97% were white, 2.6% were greater than or equal to 65 years of age. Five hundred and twenty patients were treated with budesonide capsules (enteric coated) 9 mg (total daily dose). The most common adverse reactions reported were headache, respiratory infection, nausea, and symptoms of hypercorticism. Clinical studies have shown that the frequency of glucocorticosteroid-associated adverse reactions was substantially reduced with budesonide capsules (enteric coated) compared with prednisolone at therapeutically equivalent doses. Adverse reactions occurring in greater than or equal to 5% of the patients are listed in Table 1:

The safety of budesonide capsules (enteric coated) was evaluated in 233 patients in four long-term clinical trials (52 weeks). A total of 145 patients were treated with budesonide capsules (enteric coated) 6 mg. A total of 8% of budesonide capsule (enteric coated) patients discontinued treatment due to adverse reactions compared with 10% in the placebo group. The adverse reaction profile in long-term treatment of Crohn’s disease was similar to that of short-term treatment with budesonide capsules (enteric coated) 9 mg in active Crohn’s disease.

In the long-term clinical trials, the following adverse reactions occurred in greater than or equal to 5% of the 6 mg budesonide capsule (enteric coated) patients and are not listed in (Table 1) or by body system below: diarrhea (10%); sinusitis (8%); infection viral (6%); and arthralgia (5%).

Adverse reactions, occurring in patients treated with budesonide capsules (enteric coated) 9 mg (total daily dose) in short-term active disease state studies and/or budesonide capsules (enteric coated) 6 mg (total daily dose) long-term, with an incidence less than 5% and greater than placebo are listed below by system organ class:

 

leukocytosis Blood and lymphatic system disorders:

 

palpitation, tachycardia Cardiac disorders:

 

eye abnormality, vision abnormal Eye disorders:

 

asthenia, chest pain, dependent edema, face edema, flu-like disorder, malaise, fever General disorders and administration site conditions:

 

anus disorder, Crohn’s disease aggravated, enteritis, epigastric pain, gastrointestinal fistula, glossitis, hemorrhoids, intestinal obstruction, tongue edema, tooth disorder Gastrointestinal disorders:

 

Ear infection-not otherwise specified, bronchitis, abscess, rhinitis, urinary tract infection, thrush Infections and infestations:

 

c-reactive protein increased, weight increased Investigations:

 

appetite increased, hypokalemia Metabolism and nutrition disorders:

 

arthritis, cramps, myalgia Musculoskeletal and connective tissue disorders:

 

hyperkinesia, parasthesia, tremor, vertigo, dizziness, somnolence, amnesia Nervous system disorders:

 

agitation, confusion, insomnia, nervousness, sleep disorder Psychiatric disorders:

 

dysuria, micturition frequency, nocturia Renal and urinary disorders:

 

intermenstrual bleeding, menstrual disorder Reproductive system and breast disorders:

 

dyspnea, pharynx disorder Respiratory, thoracic and mediastinal disorders:

 

acne, alopecia, dermatitis, eczema, skin disorder, sweating increased, purpura Skin and subcutaneous tissue disorders:

 

flushing, hypertension Vascular disorders:

Table 2 displays the frequency and incidence of signs/symptoms of hypercorticism by active questioning of patients in short-term clinical trials.

Table 3 displays the frequency and incidence of signs/symptoms of hypercorticism by active questioning of patients in long-term clinical trials.

The incidence of signs/symptoms of hypercorticism as described above in long-term clinical trials was similar to that seen in the short-term clinical trials.

A randomized, open, parallel-group multicenter safety study 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.

6.2 Postmarketing Experience

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.

 

Anaphylactic reactions Immune System Disorders:

 

Benign intracranial hypertension Nervous System Disorders:

 

Mood swings Psychiatric Disorders:

8.1 Pregnancy

8.3 Nursing Mothers

The disposition of budesonide when delivered by inhalation from a dry powder inhaler at doses of 200 or 400 mcg twice daily for at least 3 months was studied in eight lactating women with asthma from 1 to 6 months postpartum . Systemic exposure to budesonide in these women appears to be comparable to that in non-lactating women with asthma from other studies. Breast milk obtained over eight hours post-dose revealed that the maximum budesonide concentration for the 400 and 800 mcg total daily doses was 0.39 and 0.78 nmol/L, respectively, and occurred within 45 minutes after inhalation. The estimated oral daily dose of budesonide from breast milk to the infant is approximately 0.007 and 0.014 mcg/kg per day for the two dose regimens used in this study, which represents approximately 0.3% to 1% of the dose inhaled by the mother. Budesonide plasma concentrations obtained from five infants at about 90 minutes after breast feeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels (less than 0.02 nmol/L in four infants and less than 0.04 nmol/L in one infant). 1

The recommended daily dose of budesonide capsules (enteric coated) is higher (up to 9 mg daily) compared with inhaled budesonide (up to 800 mg daily) given to mothers in the above 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 mg daily dose of inhaled budesonide at steady state in the above inhalation study.

Since there are no data from controlled trials on the use of budesonide capsules (enteric coated) by nursing mothers or their infants, and because of the potential for serious adverse reactions in nursing infants from budesonide capsules (enteric coated), a decision should be made whether to discontinue nursing or to discontinue budesonide capsules (enteric coated), taking into account the clinical importance of budesonide capsules (enteric coated) to the mother.

Budesonide is secreted in human milk. Data from budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide available in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother. 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.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Systemic and inhaled corticosteroids, including budesonide capsules (enteric coated), may cause a reduction of growth velocity in pediatric patients.

8.5 Geriatric Use

Clinical studies of budesonide capsules (enteric coated) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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.

8.6 Hepatic Insufficiency

Patients with moderate to severe liver disease should be monitored for increased signs and/or symptoms of hypercorticism. Reducing the dose of budesonide capsules (enteric coated) should be considered in these patients [ ]. see Warnings and Precautions (5.4)

12.1 Mechanism of Action

Budesonide has a high topical glucocorticosteroid (GCS) activity and a substantial first pass elimination. The formulation contains granules which are coated to protect dissolution in gastric juice, but which dissolve at pH greater than 5.5, i.e., normally when the granules reach the duodenum. Thereafter, a matrix of ethylcellulose with budesonide controls the release of the drug into the intestinal lumen in a time-dependent manner.

12.2 Pharmacodynamics

Budesonide has a high glucocorticoid effect and a weak mineralocorticoid effect, and the affinity of budesonide to GCS receptors, which reflects the intrinsic potency of the drug, is about 200-fold that of cortisol and 15-fold that of prednisolone.

Treatment with systemically active GCS is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function. Markers, indirect and direct, of this are cortisol levels in plasma or urine and response to ACTH stimulation.

Plasma cortisol suppression was compared following 5 days’ administration of budesonide capsules (enteric coated) and prednisolone in a crossover study in healthy volunteers. The mean decrease in the integrated 0 to 24 hour plasma cortisol concentration was greater (78%) with prednisolone 20 mg per day compared to 45% with budesonide capsules (enteric coated) 9 mg per day.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with budesonide were conducted in rats and mice. In a 2-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 2-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 sex-linked recessive lethality test, the rat hepatocyte UDS test and the mouse micronucleus test. +/-Drosophila melanogaster

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).

17.1 Hypercorticism and Adrenal Suppression

Patients should be advised that budesonide capsules (enteric coated) may cause systemic glucocorticosteroid effects of hypercorticism and adrenal suppression. Patients should taper slowly from systemic glucocorticosteroids if transferring to budesonide capsules (enteric coated) [ ]. see and Warnings and Precautions (5.1)(5.2)

17.2 Immunosuppression

Patients who are on immunosuppressant doses of glucocorticosteroids should be warned to avoid exposure to chicken pox or measles and, if exposed, to consult their physician without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral or parasitic infections [ ]. see Warnings and Precautions (5.3)

17.3 How to Take Budesonide Capsules (enteric coated)

Budesonide capsules (enteric coated) should be swallowed whole and NOT CHEWED OR BROKEN. Patients should be advised to avoid the consumption of grapefruit juice for the duration of their budesonide capsules (enteric coated) therapy.