ENTOCORT

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 for oral administration 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.

12 CLINICAL PHARMACOLOGY

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, 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.

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 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 per day compared to 45% with ENTOCORT EC 9 mg per day.

12.3 Pharmacokinetics

Absorption

The absorption of ENTOCORT EC seems to be complete, although C_max and T_max 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 16α-hydroxy prednisolone. The glucocorticoid activity of these metabolites is negligible (less than 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 _1/2, after administration of intravenous doses ranges between 2 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

Gender

No significant pharmacokinetic differences have been identified due to gender.

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 (less than 1/100).

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) [ see Drug Interactions (7) ].

Since the dissolution of the coating of ENTOCORT EC is pH dependent (dissolves at pH greater than 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 once daily 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.

13 NONCLINICAL TOXICOLOGY

13.1 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 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).

14 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 greater than or equal to 65 years of age and none were greater than 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 less than or equal to 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 reactions. A checklist of potential symptoms of hypercorticism was used.

One study (Study 1) compared the safety and efficacy of ENTOCORT EC 9 mg daily in the morning to a comparator. At baseline, the median CDAI was 272. ENTOCORT EC 9 mg daily resulted in a significantly higher clinical improvement rate at Week 8 than the comparator. See Table 4.

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 twice daily, 4.5 mg twice daily, or 7.5 mg twice daily) 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 4), 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 daily nor 4.5 mg twice daily ENTOCORT EC dose levels was statistically different from placebo (Table 4).

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 daily 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 4).

The proportion of patients with normal plasma cortisol values (greater than 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 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 ENTOCORT EC 6 mg per day. ENTOCORT EC 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% vs. 45% for placebo).

16 HOW SUPPLIED/STORAGE AND HANDLING

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 and are supplied as follows:

NDC 0186–0702–10 Bottles of 100

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

Keep container tightly

17 PATIENT COUNSELING INFORMATION

“See FDA-Approved Patient Labeling (Patient Information)”

Patients being treated with ENTOCORT EC Capsules should receive the following information and instructions. This information is intended to aid the patient in the safe and effective use of the medication. It is not a disclosure of all possible adverse or intended effects. For proper use of ENTOCORT EC Capsules and to attain maximum improvement, the patient should read and follow the accompanying FDA-Approved Patient Labeling.

17.1 Hypercorticism and adrenal suppression

Patients should be advised that ENTOCORT EC Capsules may cause systemic glucocorticosteroid effects of hypercorticism and adrenal suppression. Patients should taper slowly from systemic glucocorticosteroids if transferring to ENTOCORT EC Capsules [see Warnings and Precautions (5.1)and (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 ENTOCORT EC Capsules

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.

ENTOCORT is a trademark of the AstraZeneca group of companies.

©AstraZeneca 2010, 2011

Distributed by:

AstraZeneca LP

Wilmington, DE 19850

PATIENT INFORMATION

ENTOCORT EC (EN-toe-cort EE CEE)

(budesonide)

Capsules

Read the Patient Information that comes with ENTOCORT EC before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is ENTOCORT EC?

ENTOCORT EC is a prescription glucocorticosteroid medicine used in people with mild to moderate Crohn’s disease that affects part of the small intestine (ileum) and part of the large intestine (ascending colon):

• •to treat active Crohn’s disease.
• •to help keep symptoms from coming back for up to 3 months.

It is not known if ENTOCORT EC is safe and effective in children.

Who should not take ENTOCORT EC?

Do not take ENTOCORT EC if:

• •you are allergic to budesonide or any of the ingredients in ENTOCORT EC. See the end of this leaflet for a complete list of ingredients in ENTOCORT EC.

What should I tell my healthcare provider before taking ENTOCORT EC?

Before you take ENTOCORT EC tell your healthcare provider if you:

• •have liver problems
• •are planning to have surgery
• •have chicken pox or measles or have recently been near anyone with chicken pox or measles
• •have or had a family history of diabetes, cataracts or glaucoma
• •have or had tuberculosis
• •have high blood pressure (hypertension)
• •have decreased bone mineral density (osteoporosis)
• •stomach ulcers
• •any other medical condition
• •are pregnant or plan to become pregnant. It is not known if ENTOCORT EC may harm your unborn baby.
• •are breastfeeding or plan to breastfeed. ENTOCORT EC can pass into breast milk and may harm your baby. You and your healthcare provider should decide if you will take ENTOCORT EC or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. ENTOCORT EC and other medicines may affect each other causing side effects.

Especially tell your healthcare provider if you take:

• •a glucocorticosteroid medicine
• •medicines that suppress your immune system (immunosuppressant)
• •ketoconazale or other medicines that affect how your liver works.

Ask your healthcare provider or pharmacist if you are not sure if your medicine is one listed above.

How should I take ENTOCORT EC?

• •Take ENTOCORT EC exactly as your healthcare provider tells you.
• •Your healthcare provider will tell you how many ENTOCORT EC capsules to take. Your healthcare provider may change your dose if needed.
• •Take ENTOCORT EC in the morning.
• •Take ENTOCORT EC capsules whole. Do not chew or crush ENTOCORT EC capsules before swallowing.

What should I avoid while taking ENTOCORT EC?

• •Do not eat grapefruit or drink grapefruit juice while taking ENTOCORT EC. Eating grapefruit or drinking grapefruit juice can increase the level of ENTOCORT EC in your blood.

What are the possible side effects of ENTOCORT EC?

• • Effects of having too much glucocorticosteroid medicine in your blood (hypercorticism). Long-time use of ENTOCORT EC can cause you to have too much glucocorticosteroid medicine in your blood. Tell your healthcare provider if you have any of the following signs and symptoms of hypercorticism:
  • oacne
  • obruise easily
  • orounding of your face (moon face)
  • oankle swelling
  • othicker or more hair on your body and face
  • oa fatty pad or hump between your shoulders (buffalo hump)
  • opink or purple stretch marks on the skin of your abdomen, thighs, breasts and arms
• • Adrenal suppression. When ENTOCORT EC is taken for a long period of time (chronic use), adrenal suppression can happen. This is a condition in which the adrenal glands do not make enough steroid hormones. Symptoms of adrenal suppression include: tiredness, weakness, nausea and vomiting and low blood pressure. Tell your healthcare provider if you are under stress or have any symptoms of adrenal suppression during treatment with ENTOCORT EC.
• • Immune system effects and a higher chance of infections.
  ENTOCORT EC weakens your immune system. Taking medicines that weaken your immune system makes you more likely to get infections. Avoid contact with people who have contagious diseases such as chicken pox or measles, while taking ENTOCORT EC.

Tell your healthcare provider about any signs or symptoms of infection during treatment with ENTOCORT EC, including:

The most common side effects of ENTOCORT EC include:

• •headache
• •infection in your air passages (respiratory infection)
• •back pain
• •upset stomach
• •dizziness
• •abdominal pain
• •excessive stomach or intestinal gas
• •diarrhea
• •sinus infection
• •viral infection
• •joint pain

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of ENTOCORT EC. For more information, ask your healthcare provider or pharmacist.

Call your healthcare provider for medical advice about side effects. You may report side effects to AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

How should I store ENTOCORT EC?

• •Store ENTOCORT EC at 59°F to 86°F (15°C to 30°C).
• •Keep ENTOCORT EC in a tightly closed container.

Keep ENTOCORT EC and all medicines out of reach from children.

General information about ENTOCORT EC.

Medicines are sometimes prescribed for purposes other than those listed 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.

This Patient Information leaflet summarizes the most important information about ENTOCORT EC. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about ENTOCORT EC that is written for health professionals.

For more information go to.www.ENTOCORTEC.com or call 1-800-236-9933.

What are the ingredients in ENTOCORT EC?

Active ingredient: budesonide

Inactive ingredients: ethylcellulose, acetyltributyl citrate, methacrylic acid copolymer type C, triethyl citrate, antifoam M, polysorbate 80, talc, and sugar spheres.

The capsule shell contains: gelatin, iron oxide, and titanium dioxide.

Distributed by:

AstraZeneca LP

Wilmington, DE 19850

This Patient Information has been approved by the U.S. Food and Drug Administration.

Revised: December 2011

ENTOCORT is a trademark of the AstraZeneca group of companies.

© AstraZeneca 2010, 2011

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL – 3 mg Capsules

NDC 0186-0702-10

ENTOCORT^® EC

(budesonide)

3 mg Capsules

Rx Only

Manufactured for AstraZeneca LP

Wilmington, DE 19850

Product of Netherlands

AstraZeneca