Budesonide

Budesonide, USP is a white to almost white crystalline powder that is freely soluble in methylene chloride, sparingly soluble in alcohol and practically insoluble in water. 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: acetyltributyl citrate, colloidal silicon dioxide, crospovidone, dimethicone, ethylcellulose, FD&C Red No. 40 Aluminum Lake, gelatin, lactose monohydrate, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sodium hydroxide, sodium lauryl sulfate, talc, titanium dioxide and triethyl citrate.

The imprinting ink contains the following: black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, Propylene Glycol and shellac glaze.

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, 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

Absorption

The absorption of budesonide capsules (enteric coated) 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% to 90%). In vitro experiments in human liver microsomes demonstrate that budesonide is rapidly and extensively biotransformed, mainly by CYP3A4, to its two 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 to 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 8-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 (i.e., ethinyl estradiol) [see Drug Interactions (7) ].

Since the dissolution of the coating of budesonide capsules (enteric coated) 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 budesonide capsules (enteric coated). 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 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 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 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 five 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 budesonide capsules (enteric coated), 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 five 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 five 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 safety and 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 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 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 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 budesonide capsule (enteric coated) 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 budesonide capsule (enteric coated) dose levels was statistically different from placebo (Table 4).

Two clinical trials (Studies 4 and 5) compared budesonide capsules (enteric coated) 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 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 4).

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

The efficacy and safety 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 four 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 four studies at 3 months (28% vs. 45% for placebo).

16 HOW SUPPLIED/STORAGE AND HANDLING

Budesonide Capsules (enteric coated) are available as 3 mg capsules.

The 3 mg capsule is a red opaque cap/red opaque body, hard-shell gelatin capsule filled with white to off-white enteric-coated pellets with no markings. The capsule is axially printed with MYLAN over 7155 in black ink on both the cap and body. They are available as follows:

NDC 0378-7155-01
bottles of 100 capsules

NDC 0378-7155-05
bottles of 500 capsules

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

PHARMACIST: Dispense a Patient Information Leaflet with each prescription.

17 PATIENT COUNSELING INFORMATION

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

Patients being treated with budesonide capsules (enteric coated) 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 budesonide capsules (enteric coated) 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 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 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 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.

PATIENT INFORMATION LEAFLET
BUDESONIDE CAPSULES (enteric coated)
(bue des' oh nide)
3 mg

Read the Patient Information that comes with budesonide capsules (enteric coated) 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 are budesonide capsules (enteric coated)?

Budesonide capsules (enteric coated) are 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 budesonide capsules (enteric coated) are safe and effective in children.

Who should not take budesonide capsules (enteric coated)?

Do not take budesonide capsules (enteric coated) if:

• •you are allergic to budesonide or any of the ingredients in budesonide capsules (enteric coated). See the end of this leaflet for a complete list of ingredients in budesonide capsules (enteric coated).

What should I tell my healthcare provider before taking budesonide capsules (enteric coated)?

Before you take budesonide capsules (enteric coated) 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 budesonide capsules (enteric coated) may harm your unborn baby.
• •are breastfeeding or plan to breastfeed. Budesonide can pass into breast milk and may harm your baby. You and your healthcare provider should decide if you will take budesonide capsules (enteric coated) 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. Budesonide capsules (enteric coated) 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 budesonide capsules (enteric coated)?

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

What should I avoid while taking budesonide capsules (enteric coated)?

• •Do not eat grapefruit or drink grapefruit juice while taking budesonide capsules (enteric coated). Eating grapefruit or drinking grapefruit juice can increase the level of budesonide in your blood.

What are the possible side effects of budesonide capsules (enteric coated)?

• • Effects of having too much glucocorticosteroid medicine in your blood (hypercorticism). Long-time use of budesonide capsules (enteric coated) 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 budesonide capsules (enteric coated) are 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 budesonide capsules (enteric coated).
• • Immune system effects and a higher chance of infections. Budesonide capsules (enteric coated) weaken 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 budesonide capsules (enteric coated).
  Tell your healthcare provider about any signs or symptoms of infection during treatment with budesonide capsules (enteric coated), including:
  • ofever
  • opain
  • oaches
  • ochills
  • ofeeling tired
  • onausea and vomiting
• • Worsening of allergies. If you take certain other glucocorticosteroid medicines to treat allergies, switching to budesonide capsules (enteric coated) may cause your allergies to come back. These allergies may include eczema (a skin disease) or rhinitis (inflammation inside your nose). Tell your healthcare provider if any of your allergies become worse while taking budesonide capsules (enteric coated).

The most common side effects of budesonide capsules (enteric coated) 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 budesonide capsules (enteric coated). 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 Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

How should I store budesonide capsules (enteric coated)?

• •Store budesonide capsules (enteric coated) at 20° to 25°C (68° to 77°F).
• •Keep budesonide capsules (enteric coated) in a tightly closed container.

Keep budesonide capsules (enteric coated) and all medicines out of reach from children.

General information about budesonide capsules (enteric coated).

Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use budesonide capsules (enteric coated) for a condition for which it was not prescribed. Do not give budesonide capsules (enteric coated) 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 budesonide capsules (enteric coated). If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about budesonide capsules (enteric coated) that is written for health professionals.

For more information call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

What are the ingredients in budesonide capsules (enteric coated)?

Active ingredient: budesonide, USP

Inactive ingredients: acetyltributyl citrate, colloidal silicon dioxide, crospovidone, dimethicone, ethylcellulose, FD&C Red No. 40 Aluminum Lake, gelatin, lactose monohydrate, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sodium hydroxide, sodium lauryl sulfate, talc, titanium dioxide and triethyl citrate.

The imprinting ink contains the following: black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, Propylene Glycol and shellac glaze.

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

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

REVISED FEBRUARY 2014
BUDE:R2ppt

PRINCIPAL DISPLAY PANEL – 3 mg

NDC 0378-7155-01

Budesonide
Capsules
3 mg
Enteric Coated

PHARMACIST: Dispense the accompanying
Patient Information Leaflet to each patient.

Rx only 100 Capsules

Each capsule contains:
Budesonide, USP 3 mg

Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication
out of the reach of children.

Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]

Usual Dosage: Take 3 capsules
every morning. See prescribing
information.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Mylan.com

RM7155A1