Budesonide, the active ingredient of ENTOCORT® EC capsules, is a synthetic corticosteroid. It 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 empirical formula of budesonide is C₂₅H₃₄O₆ and its molecular weight is 430.5. Its structural formula is:

Budesonide is a white to off-white, tasteless, odorless powder that is practically insoluble in water and heptane, sparingly soluble in ethanol, and freely soluble in chloroform. Its partition coefficient between octanol and water at pH 5 is 1.6 x 10³ ionic strength 0.01.

Each capsule contains 3 mg of micronized budesonide with the following inactive ingredients: ethylcellulose, acetyltributyl citrate, methacrylic acid copolymer type C, triethyl citrate, antifoam M, polysorbate 80, talc, and sugar spheres. The capsule shells have the following inactive ingredients: gelatin, iron oxide, and titanium dioxide.

ENTOCORT EC is indicated for

•  the treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon and
•  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.

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 taken once daily in the morning for up to 8 weeks.

Repeated 8 week courses of ENTOCORT EC can be given for recurring episodes of active disease.

Following an 8 week course(s) of treatment for active disease and once the patient's symptoms are controlled (CDAI <150), ENTOCORT EC 6 mg 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 ENTOCORT EC 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 ENTOCORT EC with no reported episodes of adrenal insufficiency. Since prednisolone should not be stopped abruptly, tapering should begin concomitantly with initiating ENTOCORT EC treatment.

Hepatic Insufficiency: Patients with moderate to severe liver disease should be monitored for increased signs and/or symptoms of hypercorticism. Reducing the dose of ENTOCORT EC capsules should be considered in these patients.

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. Reduction in the dose of ENTOCORT EC capsules should be considered.

ENTOCORT EC capsules should be swallowed whole and not chewed or broken.

ENTOCORT EC 3 mg capsules are hard gelatin capsules with an opaque light grey body and an opaque pink cap, coded with ENTOCORT EC 3 mg on the capsule.

They are supplied as follows:

NDC 65483-702-10 Bottles of 100

Storage

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room Temperature].

Keep container tightly closed.

Manufactured by AstraZeneca AB S-151 85 Sodertalje, Sweden. Distributed by: Prometheus Laboratories Inc San Diego, CA 92121. Rev 04/05. FDA rev date: 4/29/2005

The safety of ENTOCORT EC 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 ≥ 65 years of age. Five hundred and twenty patients were treated with ENTOCORT EC 9 mg (total daily dose). In general, ENTOCORT EC was well tolerated in these trials. The most common adverse events reported were headache, respiratory infection, nausea, and symptoms of hypercorticism. Clinical studies have shown that the frequency of glucocorticosteroid-associated adverse events was substantially reduced with ENTOCORT EC capsules compared with prednisolone at therapeutically equivalent doses. Adverse events occurring in ≥ 5% of the patients are listed in Table 2:

Table 2: Adverse Events Occurring in ≥ 5% of the Patients in any Treated Group

The safety of ENTOCORT EC was evaluated in 233 patients in four long-term clinical trials (52 weeks). A total of 145 patients were treated with ENTOCORT EC 6 mg. A total of 8% of ENTOCORT EC patients discontinued treatment due to adverse events compared with 10% in the placebo group. The adverse event profile in long-term treatment of Crohn's disease was similar to that of short-term treatment with ENTOCORT EC 9 mg in active Crohn's disease.

In the long-term clinical trials, the following adverse events occurred in ≥ 5% of the 6 mg ENTOCORT EC patients and are not listed in Table 2 or by body system below: diarrhea (10%); sinusitis (8%); infection viral (6%); and arthralgia (5%).

Adverse events, occurring in 520 patients treated with ENTOCORT EC 9 mg (total daily dose) in short-term active disease state studies, with an incidence of <5% and greater than placebo (n=107), are listed below by body system:

Body as a Whole: asthenia, C-Reactive protein increased, chest pain, dependent edema, face edema, flu-like disorder, malaise; Cardiovascular: hypertension; Central and Peripheral Nervous System: hyperkinesia, paresthesia, tremor, vertigo; Gastrointestinal: anus disorder, Crohn's disease aggravated, enteritis, epigastric pain, gastrointestinal fistula, glossitis, hemorrhoids, intestinal obstruction, tongue edema, tooth disorder; Hearing and Vestibular: ear infection-not otherwise specified; Heart Rate and Rhythm: palpitation, tachycardia; Metabolic and Nutritional: hypokalemia, weight increase; Musculoskeletal: arthritis aggravated, cramps, myalgia; Psychiatric: agitation, appetite increased, confusion, insomnia, nervousness, sleep disorder, somnolence; Reproductive, Female: intermenstrual bleeding, menstrual disorder; Respiratory: bronchitis, dyspnea; Skin and Appendages: acne, alopecia, dermatitis, eczema, skin disorder, sweating increased; Urinary: dysuria, micturition frequency, nocturia; Vascular: flushing; Vision: eye abnormality, vision abnormal; White Blood Cell: leukocytosis.

For the 145 patients treated with ENTOCORT EC 6 mg (total daily dose) in long-term studies, the following adverse events that are not included in the list above occurred with an incidence <5% but >2% and greater than for placebo: abscess, amnesia, dizziness, fever, pharynx disorder, purpura, rhinitis, and urinary tract infection.

Glucocorticosteroid Adverse Reactions

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

Table 3: Summary and Incidence of Symptoms of Hypercorticism in Short-Term Studies

In addition to the symptoms in Table 3, three cases of benign intracranial hypertension have been reported in patients treated with budesonide from post-marketing surveillance. A cause and effect relationship has not been established.

Table 4 displays the frequency and incidence of symptoms of hypercorticism by active questioning of patients in long-term clinical trials.

Table 4: Summary and Incidence of Symptoms of Hypercorticism in Long-Term Studies

The incidence of 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 ENTOCORT EC (<9 mg/day) and prednisolone (<40 mg/day) on bone mineral density over 2 years when used at doses adjusted to disease severity. Bone mineral density decreased significantly less with ENTOCORT EC than with prednisolone in steroid-naive patients, whereas no difference could be detected between treatment groups for steroid-dependent patients and previous steroid users. The incidence of treatment-emergent symptoms of 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 ENTOCORT EC, were reported in ≥ 1% of patients: hypokalemia, leukocytosis, anemia, hematuria, pyuria, erythrocyte sedimentation rate increased, alkaline phosphatase increased, atypical neutrophils, C-reactive protein increased, and adrenal insufficiency.

Concomitant oral administration of ketoconazole (a known inhibitor of CYP3A4 activity in the liver and in the intestinal mucosa) caused an eight-fold increase of the systemic exposure to oral budesonide. If treatment with inhibitors of CYP3A4 activity (such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, etc.) is indicated, reduction of the budesonide dose should be considered. After extensive intake of grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure for oral budesonide increased about two times. As with other drugs primarily being metabolized through CYP3A4, ingestion of grapefruit or grapefruit juice should be avoided in connection with budesonide administration.

Glucocorticosteroids can reduce the response of the hypo-thalamus-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 ENTOCORT EC is a glucocorticosteroid, general warnings concerning glucocorticoids should be followed.

Care is needed in patients who are transferred from glucocorticosteroid treatment with high systemic effects to corticosteroids with lower systemic availability, 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 systemic steroid should be reduced cautiously.

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 the respective package insert for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents may be considered.

General

Caution should be taken in patients with tuberculosis, 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.

Replacement of systemic glucocorticosteroids with ENTOCORT EC capsules may unmask allergies, eg, rhinitis and eczema, which were previously controlled by the systemic drug.

When ENTOCORT EC capsules are used chronically, systemic glucocorticosteroid effects such as hypercorticism and adrenal suppression may occur.

Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis.

Information for Patients

ENTOCORT EC capsules 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 ENTOCORT EC therapy.

Patients should be given the patient package insert for additional information.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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 mela-nogaster 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).

Pregnancy

Teratogenic Effects: Pregnancy Category C: As with other corticosteroids, budesonide was teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at subcutaneous doses of 25 mcg/kg in rabbits (approximately 0.05 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).

There are no adequate and well-controlled studies in pregnant women. Budesonide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully observed.

Nursing Mothers

Glucocorticosteroids are secreted in human milk. Because of the potential for adverse reactions in nursing infants from any corticosteroid, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. The amount of budesonide secreted in breast milk has not been determined.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of ENTOCORT EC 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.

Reports of acute toxicity and/or death following overdosage of glucocorticosteroids are rare. Treatment consists of immediate gastric lavage or emesis followed by supportive and symptomatic therapy.

If glucocorticosteroids are used at excessive doses for prolonged periods, systemic glucocorticosteroid effects such as hypercorticism and adrenal suppression may occur. For chronic overdosage in the face 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.

ENTOCORT EC is contraindicated in patients with known hypersensitivity to budesonide.

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 >5.5, ie, 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.

Pharmacokinetics

Absorption

The absorption of ENTOCORT EC seems to be complete, although Cmax and Tmax are variable. Time to peak concentration varies in individual patients between 30 and 600 minutes. Following oral administration of 9 mg of budesonide in healthy subjects, a peak plasma concentration of approximately 5 nmol/L is observed and the area under the plasma concentration time curve is approximately 30 nmol-hr/L. The systemic availability after a single dose is higher in patients with Crohn's disease compared to healthy volunteers, (21% vs 9%) but approaches that in healthy volunteers after repeated dosing.

Distribution

The mean volume of distribution (V_ss) of budesonide varies between 2.2 and 3.9 L/kg in healthy subjects and in patients. Plasma protein binding is 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 is about 0.8.

Metabolism

Following absorption, budesonide is subject to high first pass metabolism (80-90%). In vitro experiments in human liver microsomes demonstrate that budesonide is rapidly and extensively biotransformed, mainly by CYP3A4, to its 2 major metabolites, 6β-hydroxy budesonide and 16a-hydroxy prednisolone. The glucocorticoid activity of these metabolites is negligible (<1/100) in relation to that of the parent compound.

In vivo investigations with intravenous doses in healthy subjects are in agreement with the in vitro findings and demonstrate that budesonide has a high plasma clearance, 0.9-1.8 L/min. Similarly, high plasma clearance values have been shown in patients with Crohn's disease. These high plasma clearance values approach the estimated liver blood flow, and, accordingly, suggest that budesonide is a high hepatic clearance drug.

The plasma elimination half-life, t_½, after administration of intravenous doses ranges between 2.0 and 3.6 hours, and does not differ between healthy adults and patients with Crohn's disease.

Excretion

Budesonide is 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 is 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 is detected in urine.

Special Populations

No significant pharmacokinetic differences have been identified due to sex.

Hepatic Insufficiency

In patients with liver cirrhosis, systemic availability of orally administered budesonide correlates with disease severity and is, on average, 2.5-fold higher compared with healthy controls. Patients with mild liver disease are minimally affected. Patients with severe liver dysfunction were not studied. Absorption parameters are not altered, and for the intravenous dose, no significant differences in CL or V_ss are observed.

Renal Insufficiency

The pharmacokinetics of budesonide in patients with renal impairment has not been studied. Intact budesonide is not renally excreted, but metabolites are to a large extent, and might therefore reach higher levels in patients with impaired renal function. However, these metabolites have negligible corticosteroid activity as compared with budesonide (<1/100). Thus, patients with impaired renal function taking budesonide are not expected to have an increased risk of adverse effects.

Drug-Drug Interactions

Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase the plasma levels of budesonide several-fold. Co-administration of ketoconazole results in an eight-fold increase in AUC of budesonide, compared to budesonide alone. Grapefruit juice, an inhibitor of gut mucosal CYP3A, approximately doubles the systemic exposure of oral budesonide. Conversely, induction of CYP3A4 can result in the lowering of budesonide plasma levels. Oral contraceptives containing ethinyl estradiol, which are also metabolized by CYP3A4, do not affect the pharmacokinetics of budesonide. Budesonide does not affect the plasma levels of oral contraceptives (ie, ethinyl estradiol).

Since the dissolution of the coating of ENTOCORT EC is pH dependent (dissolves at pH >5.5), the release properties and uptake of the compound may be altered after treatment with drugs that change the gastrointestinal pH. However, the gastric acid inhibitory drug omeprazole, 20 mg qd, does not affect the absorption or pharmacokinetics of ENTOCORT EC. When an uncoated oral formulation of budesonide is co-administered with a daily dose of cimetidine 1 g, a slight increase in the budesonide peak plasma concentration and rate of absorption occurs, resulting in significant cortisol suppression.

Food Effects

A mean delay in time to peak concentration of 2.5 hours is observed with the intake of a high-fat meal, with no significant differences in AUC.

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 five days' administration of ENTOCORT EC capsules and prednisolone in a crossover study in healthy volunteers. The mean decrease in the integrated 0-24 hour plasma cortisol concentration was greater (78%) with prednisolone 20 mg/day compared to 45% with ENTOCORT EC 9 mg/day.

Clinical Studies

The safety and efficacy of ENTOCORT EC 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. The study patients ranged in age from 17 to 85 (mean 35), 40% were male and 97% were white. Of the 651 patients treated with ENTOCORT EC, 17 (2.6%) were ≥ 65 years of age and none were >74 years of age. The Crohn's Disease Activity Index (CDAI) was the main clinical assessment used for determining efficacy in these 5 studies. 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 ≤ 150 assessed after 8 weeks of treatment, was the primary efficacy variable in these 5 comparative efficacy studies of ENTOCORT EC capsules. Safety assessments in these studies included monitoring of adverse experiences. A checklist of potential symptoms of hypercorticism was used.

One study (Study 1) compared the safety and efficacy of ENTOCORT EC 9 mg qd in the morning to a comparator. At baseline, the median CDAI was 272. ENTOCORT EC 9 mg qd resulted in a significantly higher clinical improvement rate at Week 8 than the comparator (Table 1).

Table 1: Clinical Improvement Rates (CDAI ≤ 150) After 8 weeks of Treatment

Two placebo-controlled clinical trials (Studies 2 and 3) were conducted. Study 2 involved 258 patients and tested the effects of graded doses of ENTOCORT EC (1.5 mg bid, 4.5 mg bid, or 7.5 mg bid) versus placebo. At baseline, the median CDAI was 290. The 3 mg per day dose level (data not shown) could not be differentiated from placebo. The 9 mg per day arm was statistically different from placebo (Table 1), while no additional benefit was seen when the daily ENTOCORT EC dose was increased to 15 mg per day (data not shown). In Study 3, the median CDAI at baseline was 263. Neither 9 mg qd nor 4.5 mg bid ENTOCORT EC dose levels was statistically different from placebo (Table 1).

Two clinical trials (Studies 4 and 5) compared ENTOCORT EC capsules with oral prednisolone (initial dose 40 mg per day). At baseline, the median CDAI was 277. Equal clinical improvement rates (60%) were seen in the ENTOCORT EC 9 mg qd and the prednisolone groups in Study 4. In Study 5, 13% fewer patients in the ENTOCORT EC group experienced clinical improvement than in the prednisolone group (no statistical difference) (Table 1).

The proportion of patients with normal plasma cortisol values (≥ 150 nmol/L) was significantly higher in the ENTOCORT EC groups in both trials (60 to 66%) than in the prednisolone groups (26 to 28%) at Week 8.

The efficacy and safety of ENTOCORT EC 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 ENTOCORT EC 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. ENTOCORT EC 6 mg/day prolonged the time to relapse, defined as an increase in CDAI of at least 60 units to a total score >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 ENTOCORT EC 6 mg/day. ENTOCORT EC 6 mg/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% vs. 45% for placebo).

Entocort EC
(budesonide) Capsules

Read this information carefully before you begin treatment. Read the information you get whenever you get more medicine. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about ENTOCORT EC (EN-toe-cort EE-CEE), ask your health care provider (provider). Only your provider can determine if ENTOCORT EC is right for you.

What is ENTOCORT EC?

ENTOCORT EC is a medicine to treat mild to moderate Crohn's disease in many people. However, it does not work for everyone who takes it. ENTOCORT EC is a nonsystemic corticosteroid, which means it works mainly in one area of the body. The medicine in ENTOCORT EC is released in the intestine. Therefore, it controls the symptoms of Crohn's disease even though 90% of the drug does not go into the bloodstream. Because of this, it causes fewer severe side effects than other corticosteroids. (See the end of this Patient Information for information about Crohn's disease.)

Who should not take ENTOCORT EC?

Do not take ENTOCORT EC if:

• you are breast feeding. Because ENTOCORT EC is carried in human milk, it may harm the baby. Talk with your provider about whether you should stop breast feeding to take ENTOCORT EC or should use another treatment
• you have had an allergic reaction to ENTOCORT EC or any of its ingredients

To help your provider decide if ENTOCORT EC is right for you, tell your provider:

• if you had an allergic reaction to any medicine in the past
• the names of all the prescription and nonprescription medicines you now take. Be sure to tell your provider if you take ketoconazole, which can affect processing of ENTOCORT EC by the liver, steroids such as prednisone, or any other drug that suppresses your immune system
• if you are pregnant, think you may be pregnant, or plan to get pregnant. Your provider will talk about whether ENTOCORT EC is right for you
• if you ever had liver problems. Liver problems affect the amount of ENTOCORT EC that stays in your system, and dosage may need to be changed
• if you are about to have surgery for any reason. Your dosage may need to be changed
• if you have chicken pox or measles, or any other condition that suppresses the immune system
• if you or anyone in your family has had diabetes or glaucoma
• if you ever had tuberculosis, high blood pressure, osteoporosis, ulcers, or cataracts.

How should I take ENTOCORT EC?

Take ENTOCORT EC in the morning. Swallow each ENTOCORT EC capsule whole. Do not open, chew, or crush ENTOCORT EC capsules. Your provider will tell you how long to take ENTOCORT EC.

What should I avoid while taking ENTOCORT EC?

Patients who take medicines that suppress the immune system, such as ENTOCORT EC, are more likely to get infections. Avoid people with infections. Also, if you never had chicken pox or measles, be careful to avoid people with these conditions. These conditions can be more serious if you get them while taking ENTOCORT EC.

While you are taking ENTOCORT EC, do not drink grapefruit juice regularly. Grapefruit juice can increase the amount of ENTOCORT EC in your blood. Other juices, like orange juice or apple juice, do not have this effect.

What are the side effects of ENTOCORT EC?

The most common side effects of ENTOCORT EC are headache, infection in your air passages (respiratory infection), nausea, and symptoms of hypercorticism (too much steroids in your body).

These symptoms include an increase in the size of the face and neck, acne, and bruising. Most symptoms of too much steroids in your body occur less often with ENTOCORT EC than with other steroids.

Call your provider right away if you notice itching, skin rash, fever, swelling of your face and neck, or trouble breathing while you are taking ENTOCORT EC. These may be signs that you are allergic to the medicine and you may need emergency medical help.

Switching from a systemic medicine, like prednisone, to a nonsystemic medicine, such as ENTOCORT EC, can cause allergies controlled by the systemic medicine to come back. These allergies may include eczema (a skin disease) or rhinitis (inflammation inside the nose).

Call your provider if:

• your Crohn's disease symptoms worsen during treatment
• you notice any side effects or any other symptoms that concern you

These are not all the possible side effects of ENTOCORT EC. Ask your provider or pharmacist for a complete listing of all possible side effects of ENTOCORT EC.

What is Crohn's disease?

Crohn's disease is an inflammatory bowel disease. The inflammation caused by Crohn's disease is usually found in a part of the small intestine called the ileum and in the large intestine (colon). It may also occur in any part of the gastrointestinal tract (digestive system) from the mouth to the anus (rectum). The cause of Crohn's disease is not yet known.

There are many symptoms of Crohn's disease. These include diarrhea, crampy abdominal (stomach area) pain, fever, and sometimes bleeding from the rectum. Appetite loss followed by weight loss may occur. There may also be redness and soreness of the eyes, joint pain, and sores on the skin. These symptoms may range from mild to severe.

There is no cure yet for Crohn's disease. However, it is possible for the disease to quiet down (go into remission). During these periods of remission, there may be times when the symptoms get worse. In general, people with Crohn's disease are able to lead productive lives.

General advice about prescription medicines

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use ENTOCORT EC for a condition for which it was not prescribed. Do not give ENTOCORT EC to other people, even if they have the same symptoms you have. It may harm them. Keep ENTOCORT EC and all medicines out of the reach of children.

This leaflet summarizes the most important information about ENTOCORT EC. If you would like more information, talk with your provider. You can ask your pharmacist or provider for information about ENTOCORT EC that is written for health professionals. You can also visit the ENTOCORT EC Web site at (www.EntocortEC.com) or call the information center at AstraZeneca toll-free (1-800-237-8898).

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

BUDESONIDE - ORAL

(byou-DESS-oh-nide)

COMMON BRAND NAME(S): Entocort EC

USES: This medication is used to treat mild to moderate symptoms of a bowel condition called Crohn's disease. While budesonide does not cure this condition, it may help relieve symptoms such as abdominal pain and soft/liquid stools and may decrease the need for anti-diarrhea medications. Budesonide is a corticosteroid that works by decreasing swelling (inflammation).

HOW TO USE: Read the Patient Information Leaflet provided by your pharmacist before you start using budesonide and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

Take this medication by mouth with or without food, usually once daily in the morning or as directed by your doctor. Swallow the capsules whole. Do not crush or chew the capsules. Doing so can destroy the long action of the drug and may increase side effects.

The dosage and length of treatment are based on your medical condition and response to therapy.

Avoid eating grapefruit or drinking grapefruit juice while being treated with this medication unless your doctor instructs you otherwise. Grapefruit may increase the amount of certain medications in your body. Consult your doctor or pharmacist for more details.

Use this medication regularly and exactly as prescribed in order to get the most benefit from it. To help you remember, use it at the same time each day. Do not increase your dose, take it more frequently, or use it for a longer time than prescribed because this may increase your risk of serious side effects.

Do not stop taking this medication without consulting your doctor. Some conditions may become worse when the drug is suddenly stopped. Your dose may need to be gradually decreased to prevent symptoms such as extreme tiredness, weakness, or nausea. Follow your doctor's instructions carefully. Tell your doctor immediately if you experience any of these symptoms when stopping this medication.

Inform your doctor if your condition persists or worsens.

SIDE EFFECTS: See also the Precautions section.

Headache, nausea, stomach upset, or dizziness may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: signs of infection (e.g., fever, persistent cough, persistent sore throat, frequent/painful urination), mental/mood changes (e.g., depression, mood swings, agitation, confusion), chest pain, shortness of breath, severe dizziness, fast/pounding/irregular heartbeat, headache, tingling of the hands/feet, shaking (tremor), seizures, muscle/joint cramps or pain, severe stomach/abdominal pain, easy bruising/bleeding, puffy face, unusual facial hair growth, increased thirst/urination, increased sweating, swelling of the ankles/feet, slow wound healing, thinning skin, menstrual period changes, unexpected weight gain, unusual tiredness, vision changes, black stools, vomit that looks like coffee grounds, unusual skin growths.

Tell your doctor immediately if any of these rare but very serious side effects occur: vision loss, persistent/severe headaches, speech problems, loss of coordination.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking budesonide, tell your doctor if you are allergic to it; or to other corticosteroids (e.g., prednisone); or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: diabetes, certain eye problems (cataracts, herpes infection, glaucoma), high blood pressure (hypertension), a certain heart problem (congestive heart failure), severe liver disease (cirrhosis), kidney disease, stomach/intestinal problems (e.g., diverticulitis, ulcer, ulcerative colitis), brittle bones (osteoporosis), infections (e.g., tuberculosis, threadworm), bleeding problems, history of blood clots, certain mental/mood conditions (e.g., depression, mood swings), underactive thyroid (hypothyroidism), untreated mineral imbalances (e.g., low potassium/calcium).

If you have been using other, stronger corticosteroids (e.g., prednisone) and switch to this medication, or if you have been on this medication for a long time, your body may not be able to make enough natural steroids while you are under stress due to infection, surgery or injury. Deaths have sometimes occurred during such stresses due to low steroid levels. Tell your doctor immediately if any of the following side effects occur: unusual weakness, nausea/vomiting, stomach/abdominal pain.

Consult your doctor or pharmacist for more details and inform them that you use (or have used) any type of corticosteroid. Consult your doctor or pharmacist now for advice about future stress situations. You may need to carry a supply of corticosteroid tablets as a precaution. Carry a warning card or medical ID bracelet that identifies your need for oral corticosteroids during times of stress as noted. (See Medical Alert section.) Before having surgery, tell your doctor or dentist that you are taking this medication or that you have taken it within the last 12 months.

This medication may mask signs of infection or put you at greater risk of developing very serious infections. Report any injuries or signs of infection (e.g., persistent sore throat/cough/fever, pain during urination, muscle aches, changes in sputum color) that occur during treatment.

Avoid contact with people who have chickenpox or measles unless you have previously had these diseases (e.g., in childhood). If you are exposed to one of these infections and you have not previously had it, seek immediate medical attention.

If you have diabetes, this drug may increase your blood sugar levels. Check your blood sugar levels regularly as directed by your doctor. Tell your doctor immediately if you have symptoms of high blood sugar such as increased thirst/urination. Your anti-diabetic medication or diet may need to be adjusted.

If you have a history of ulcers or take large doses of aspirin or other arthritis medication, limit alcoholic beverages while taking this drug to decrease the risk of stomach/intestinal bleeding.

This drug may make you dizzy; use caution engaging in activities requiring alertness such as driving or using machinery. Limit alcoholic beverages.

When used for extended periods, corticosteroids like budesonide may affect bone strength, especially in people who smoke, have a family history of brittle bones (osteoporosis), or take other medications that may weaken bones (e.g., phenytoin). Bone density tests may help to determine if you need medication to treat or prevent this problem. Discuss with your doctor.

Caution is advised when using this drug in children. It may slow down a child's growth rate if given for long periods. Monitor your child's height and growth rate regularly. Consult your doctor for more details.

This medication should be used only when clearly needed during pregnancy. Rarely, there have been reports of similar drugs causing harm to unborn babies. Discuss the risks and benefits with your doctor. Infants born to mothers who have been using similar medications for an extended time may have low levels of corticosteroid hormone. Tell your doctor immediately if you notice symptoms such as persistent nausea/vomiting, severe diarrhea, or weakness in your newborn.

This medication passes into breast milk. Breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: See also the How to Use section.

Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medication because very serious interactions may occur: live vaccines.

If you are currently using the medication listed above, tell your doctor or pharmacist before starting budesonide.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: drugs affecting liver enzymes that remove budesonide from your body (azole antifungals including ketoconazole and itraconazole, barbiturates including phenobarbital, cimetidine, HIV protease inhibitors including ritonavir, macrolide antibiotics including erythromycin, rifamycins including rifabutin, St. Johns wort, certain anti-seizure medicines including carbamazepine), nonsteroidal anti-inflammatory drugs (NSAIDS such as ibuprofen, naproxen), drugs for diabetes (e.g., glyburide, insulin), quinolone antibiotics (e.g., ciprofloxacin, levofloxacin), drugs that affect the immune system (e.g., cyclosporine), bupropion, aldesleukin, amphotericin B, mifepristone, licorice (glycyrrhiza).

This product may interfere with certain lab tests. Make sure laboratory personnel and all your doctors know you use this drug.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., morning cortisol levels) may be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

Lifestyle changes that may help reduce the risk of bone loss (osteoporosis) during long-term therapy include weight-bearing exercise, getting enough calcium and vitamin D, stopping smoking, and limiting alcohol. Ask your doctor about lifestyle changes that may benefit you.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.