Budesonide

Budesonide, the active ingredient of ENTOCORT EC capsules, is a synthetic corticosteroid. Budesonide is designated chemically as (RS)-11β, 16α, 17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide is provided as a mixture of two epimers (22R and 22S). The 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.

Entocort EC is formulated as hard gelatin capsules filled with enteric-coated granules that dissolve at pH greater than 5.5. 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.

The following clinically significant adverse reactions are described elsewhere in labeling:

• Hypercorticism and adrenal axis suppression [see WARNINGS AND PRECAUTIONS]
• Symptoms of steroid withdrawal in those patients transferred from other systemic corticosteroids [see WARNINGS AND PRECAUTIONS]
• Increased risk of infection [see WARNINGS AND PRECAUTIONS]
• Other corticosteroid effects [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adults

The data described below reflect exposure to ENTOCORT EC in 520 patients with Crohn’s disease, including 520 exposed to 9 mg per day (total daily dose) for 8 weeks and 145 exposed to 6 mg per day for one year in placebo controlled clinical trials. Of the 520 patients, 38% were males and the age range was 17 to 74 years.

The safety of ENTOCORT EC was evaluated in 651 adult patients in five clinical trials of 8 weeks duration in patients with active mild to moderate Crohn’s disease. The most common adverse reactions, occurring in greater than or equal to 5% of the patients, are listed in Table 1.

Table 1: Common Adverse Reactions1 in 8-Week Treatment Clinical Trials

The incidence of signs and symptoms of hypercorticism reported by active questioning of patients in 4 of the 5 short-term clinical trials are displayed in Table 2.

Table 2: Summary and Incidence of Signs/Symptoms of Hypercorticism in 8-Week Treatment ClinicalTrials

The safety of ENTOCORT EC was evaluated in 233 adult patients in four long-term clinical trials (52 weeks) of maintenance of clinical remission in patients with mild to moderate Crohn’s disease. A total of 145 patients were treated with ENTOCORT EC 6 mg once daily.

The adverse reaction profile of ENTOCORT EC 6 mg once daily in maintenance of Crohn’s disease was similar to that of short-term treatment with ENTOCORT EC 9 mg once daily in active Crohn’s disease. In the long-term clinical trials, the following adverse reactions occurred in greater than or equal to 5% and are not listed in Table 1: diarrhea (10%); sinusitis (8%); infection viral (6%); and arthralgia (5%).

Signs/symptoms of hypercorticism reported by active questioning of patients in the long-term maintenance clinical trials are displayed in Table 3.

Table 3: Summary and Incidence of Signs/Symptoms of Hypercorticism in Long-Term Clinical Trials

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

Less common adverse reactions (less than 5%), occurring in adult patients treated with ENTOCORT EC 9 mg (total daily dose) in short-term treatment clinical studies and/or ENTOCORT EC 6 mg (total daily dose) in long-term maintenance clinical trials, with an incidence are listed below by system organ class:

Cardiac disorders: palpitation, tachycardia

Eye disorders: eye abnormality, vision abnormal

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

Gastrointestinal disorders: anus disorder, enteritis, epigastric pain, gastrointestinal fistula, glossitis, hemorrhoids, intestinal obstruction, tongue edema, tooth disorder

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

Investigations: weight increased

Metabolism and nutrition disorders: appetite increased

Musculoskeletal and connective tissue disorders: arthritis, cramps, myalgia

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

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

Renal and urinary disorders: dysuria, micturition frequency, nocturia

Reproductive system and breast disorders: intermenstrual bleeding, menstrual disorder

Respiratory, thoracic and mediastinal disorders: dyspnea, pharynx disorder

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

Vascular disorders: flushing, hypertension

A randomized, open, parallel-group multicenter safety clinical trial specifically compared the effect of ENTOCORT EC (less than 9 mg per day) and prednisolone (less than 40 mg per day) on bone mineral density over 2 years when used at doses adjusted to disease severity. Bone mineral density decreased significantly less with ENTOCORT EC than with prednisolone in steroid-naïve patients, whereas no difference could be detected between treatment groups for steroid-dependent patients and previous steroid users. The incidence of symptoms associated with hypercorticism was significantly higher with prednisolone treatment.

The following potentially clinically significant laboratory changes in clinical trials, irrespective of relationship to ENTOCORT EC, were reported in greater than or equal to 1% of patients: hypokalemia, leukocytosis, anemia, hematuria, pyuria, erythrocyte sedimentation rate increased, alkaline phosphatase increased, atypical neutrophils, c-reactive protein increased and adrenal insufficiency.

Adverse reactions reported in pediatric patients 8 to 17 years of age, who weigh more than 25 kg, were similar to those reactions described above in adult patients.

Postmarketing Experience

The following adverse reactions have been reported during post-approval use of ENTOCORT EC. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: Anaphylactic reactions

Nervous System Disorders: Benign intracranial hypertension

Psychiatric Disorders: Mood swings

Mechanism Of Action

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

Pharmacodynamics

Treatment with glucocorticoids, including ENTOCORT EC is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function. There was a positive correlation between the percent (%) reduction of AUC 0-24 of plasma cortisol and systemic exposure to budesonide both in pediatric and adult patients.

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 area under the plasma cortisol concentration-time curve over 24 hour (AUC 0-24 ) was greater (78%) with prednisolone 20 mg per day compared to 45% with ENTOCORT EC 9 mg per day.

The effect of budesonide on endogenous cortisol concentrations was compared between pediatrics (n=8, aged 9 to 14 years) and adults (n=6) with active Crohn’s disease following administration of ENTOCORT EC 9 mg once daily for 7 days. Compared to baseline values before treatment, the mean decrease in the AUC 0-24 of cortisol was 64% (±18%) in pediatrics and 50% (±27%) in adults after ENTOCORT EC treatment [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS and Use In Specific Populations].

The responses to adrenocorticotropin challenge (i.e., ACTH stimulation test) was studied in pediatric patients aged 8 to 17 years, with mild to moderate active Crohn’s disease in randomized, double-blind, active control study [see Clinical Studies]. After 8 weeks of treatment with 9 mg once daily ENTOCORT EC or with prednisolone, administered at tapering doses starting from 1 mg/kg, the proportion of patients with normal response to the ACTH challenge was 6% in the budesonide group compared to none in the prednisolone group; the proportion of patients with morning p-cortisol of greater than 5 mcg/dL was 50% in the budesonide group compared to 22% in the prednisolone group. The mean morning p-cortisol was 6.3 mcg/dL in the budesonide group and 2.6 mcg/dL in the prednisolone group (Table 4).

Table 4. Proportion of Pediatric Patients 8 to 17 years old with Peak Endogenous Cortisol Levels (above 18 mcg/dL) after ACTH Stimulation and Normal Response* to ACTH Challenge Following Administration of ENTOCORT EC or Prednisolone for 8 weeks

Pharmacokinetics

Following administration of ENTOCORT EC, the time to peak concentration varied in individual patients between 30 and 600 minutes. Mean oral bioavailability of budesonide ranged from 9% to 21% both in patients and in healthy subjects, demonstrating a high first-pass elimination of the drug.

Budesonide pharmacokinetics were dose-proportional following repeated administration in the dose range of 3 to 15 mg. No accumulation of budesonide was observed following repeated dosing.

Following oral administration of 9 mg ENTOCORT EC for five days in healthy subjects, the mean peak plasma concentration and the steady state area under the plasma concentration time curve for budesonide were 5.3 ± 1.8 nmol/L and 37.0 ±14.6 nmol•hr/L, respectively.

Following administration of 9 mg ENTOCORT EC once daily in patients with active Crohn’s disease, the mean peak plasma concentration and AUC were 4.0 ±2.1 nmol/L and 35.0 ±19.8 nmol•h/L, respectively.

Concomitant administration of a high-fat meal delayed the time to peak concentration of budesonide from ENTOCORT EC by 2.3 hours but did not significantly affect the AUC in healthy subjects.

The mean volume of distribution (Vss) of budesonide varied between 2.2 and 3.9 L/kg in healthy subjects and in patients. Plasma protein binding was estimated to be 85% to 90% in the concentration range 1 to 230 nmol/L, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations was about 0.8.

Budesonide had a plasma clearance, 0.9 to 1.8 L/min in healthy adults. Mean plasma clearance after intravenous administration of budesonide in patients with Crohn’s disease was 1.0 L/min. These plasma clearance values approached the estimated liver blood flow, and, accordingly, suggest that budesonide is a high hepatic clearance drug. The plasma elimination half-life, after administration of intravenous doses ranged between 2 and 3.6 hours, and did not differ between healthy adults and patients with Crohn’s disease.

Metabolism

Following absorption, budesonide is subject to high first pass metabolism (80% to 90%). In vitro experiments in human liver microsomes demonstrated that budesonide is rapidly and extensively biotransformed, mainly by CYP3A4, to its 2 major metabolites, 6β-hydroxy budesonide and 16α-hydroxy prednisolone. The corticosteroid activity of these metabolites was negligible (less than 1/100) in relation to that of the parent compound. In vivo investigations with intravenous doses in healthy subjects were in agreement with the in vitro findings.

Excretion

Budesonide was excreted in urine and feces in the form of metabolites. After oral as well as intravenous administration of micronized [3H]-budesonide, approximately 60% of the recovered radioactivity was found in urine. The major metabolites, including 6β-hydroxy budesonide and 16α-hydroxy prednisolone, are mainly renally excreted, intact or in conjugated forms. No unchanged budesonide was detected in urine.

Specific Populations

The pharmacokinetics of budesonide were investigated in pediatric patients aged 9 to 14 years (n=8) after oral administration of ENTOCORT EC and intravenous administration of budesonide. Following administration of 9 mg ENTOCORT EC once daily for 7 days, the median time to peak plasma concentration of budesonide was 5 hours and the mean peak plasma concentration was 6.0 ± 3.5 nmol/L. The mean AUC was 41.3 ±12.2 nmol•h/L and 17% higher than that in adult patients with Crohn’s disease in the same study. The mean absolute oral availability was 9.2% (3 to 17%; n=4) in pediatric patients.

After single dose administration of intravenous budesonide (n=4), the mean volume of distribution (Vss) was 2.2 ± 0.4 L/kg and mean clearance was 0.81 ± 0.2 L/min. The mean elimination half-life was 1.9 hours in pediatric patients. The body-weight normalized clearance in pediatric patients was 20.5 mL/min/kg in comparison to 15.9 mL/min/kg in adult patients after intravenous administration [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].

In patients with mild (Child-Pugh Class A, n=4) or moderate (Child-Pugh Class B, n=4) hepatic impairment, budesonide 4 mg was administered orally as a single dose. The patients with moderate hepatic impairment had a 3.5-fold higher AUC compared to the healthy subjects with normal hepatic function while the patients with mild hepatic impairment had an approximately 1.4-fold higher AUC. The Cmax values demonstrated similar increases [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]. The increased systemic exposure in patients with mild hepatic impairment was not considered to be clinically relevant. Patients with severe liver impairment (Child-Pugh Class C) were not studied.

Drug Interaction Studies

Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase the plasma concentrations of budesonide several-fold. Conversely, induction of CYP3A4 potentially could result in the lowering of budesonide plasma concentrations.

Ketoconazole

In an open, non-randomized, cross-over study, 6 healthy subjects were given budesonide 10 mg as a single dose, either alone or concomitantly with the last ketoconazole dose of 3 days treatment with ketoconazole 100 mg twice daily. Coadministration of ketoconazole resulted in an eight-fold increase in AUC of budesonide, compared to budesonide alone [see DRUG INTERACTIONS].

Grapefruit Juice

In an open, randomized, cross-over study, 8 healthy subjects were given ENTOCORT EC capsules 3 mg, either alone, or concomitantly with 600 mL concentrated grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), on the last of 4 daily administrations. Concomitant administration of grapefruit juice resulted in a 2-fold increase of the bioavailability of budesonide compared to budesonide alone [see DRUG INTERACTIONS].

Oral Contraceptives (CYP3A4 Substrates)

In a parallel study, the pharmacokinetics of budesonide were not significantly different between healthy female subjects who received oral contraceptives containing desogestrel 0.15 mg and ethinyl estradiol 30 μg and healthy female subjects who did not receive oral contraceptives. Budesonide 4.5 mg once daily (one-half the recommended dose) for one week did not affect the plasma concentrations of ethinyl estradiol, a CYP3A4 substrate. The effect of budesonide 9 mg once daily on the plasma concentrations of ethinyl estradiol was not studied.

Omeprazole

In a study in 11 healthy subjects, performed in a double-blind, randomized, placebo controlled manner, the effect of 5 to 6 days treatment with omeprazole 20 mg once daily on the pharmacokinetics of budesonide administered as ENTOCORT EC 9 mg as a single dose was investigated. Omeprazole 20 mg once daily did not affect the absorption or pharmacokinetics of budesonide.

Cimetidine

In an open, non-randomized, cross-over study, the potential effect of cimetidine on the pharmacokinetics of budesonide was studied. Six healthy subjects received cimetidine 1 gram daily (200 mg with meals and 400 mg at night) for 2 separate 3-day periods. Budesonide 4 mg was administered either alone or on the last day of one of the cimetidine treatment periods. Co-administration of cimetidine resulted in a 52% and 31% increase in the budesonide peak plasma concentration and the AUC of budesonide, respectively.

Clinical Studies

Treatment Of Mild To Moderate Active Crohn’s Disease

The 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 of 8 weeks duration. The study patients ranged in age from 17 to 85 (mean 35), 40% were male and 97% were white. The Crohn’s Disease Activity Index (CDAI) was the main clinical assessment used for determining efficacy in these 5 studies.1 The CDAI is a validated index based on subjective aspects rated by the patient (frequency of liquid or very soft stools, abdominal pain rating and general well-being) and objective observations (number of extraintestinal symptoms, need for antidiarrheal drugs, presence of abdominal mass, body weight and hematocrit). Clinical improvement, defined as a CDAI score of less than or equal to 150 assessed after 8 weeks of treatment, was the primary efficacy variable in these 5 comparative efficacy studies of 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 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 5.

Table 5: Clinical Improvement Rates (CDAI less than or equal to 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 twice daily, 4.5 mg twice daily, or 7.5 mg twice daily) versus placebo. At baseline, the median CDAI was 290. The 1.5 mg twice daily arm (data not shown) could not be differentiated from placebo. The 4.5 mg twice daily arm was statistically different from placebo (Table 5), while no additional benefit was seen when the daily ENTOCORT EC dose was increased to 15 mg per day (data not shown). Study 3 was a 3-armed parallel group study. The groups were treated with ENTOCORT EC 9 mg once daily, ENTOCORT EC 4.5 mg twice daily and placebo for 8 weeks, followed by a 2-week double-blind taper phase. The median CDAI at baseline was 263. Neither 9 mg daily nor 4.5 mg twice daily ENTOCORT EC dose levels were statistically different from placebo (Table 5). The recommended dosage of ENTOCORT EC for the treatment of mild to moderate active Crohn’s disease involving the ileum and/or the ascending colon in adults is 9 mg once daily in the morning for up to 8 weeks [see DOSAGE AND ADMINISTRATION].

Two clinical trials (Studies 4 and 5) compared ENTOCORT EC capsules with oral prednisolone (initial dose 40 mg per day). Study 4 was a 3-armed parallel group study. The groups were treated with ENTOCORT EC 9 mg once daily, ENTOCORT EC 4.5 mg twice daily and prednisolone 40 mg (tapered dose) for 8 weeks, followed by a 4-week double blind taper phase. At baseline, the median CDAI was 277. Equal clinical improvement rates (60%) were seen in the 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 5).

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 effectiveness of ENTOCORT EC, in pediatric patients aged 8 to 17 years, who weigh more than 25 kg with mild to moderate active Crohn’s disease (defined as Crohn's Disease Activity Index (CDAI) ≥ 200) involving the ileum and/or the ascending colon, was assessed in one randomized, double-blind, active control study. This study compared ENTOCORT EC 9 mg once daily, with prednisolone, administered at tapering doses starting from 1 mg/kg. Twenty-two (22) patients were treated with ENTOCORT EC capsules and 24 patients were treated with prednisolone. After 8 weeks of treatment, 55% (95% CI: 32%, 77%) of patients treated with ENTOCORT EC reached the endpoint (CDAI ≤150), as compared to 68% (95% CI: 47%, 89%) of patients treated with prednisolone. The average number of liquid or very soft stools per day (assessed over 7 days) decreased from 1.49 at baseline to 0.96 after treatment with ENTOCORT EC and 2.00 at baseline to 0.52 after treatment with prednisolone. The average daily abdominal pain rating (where 0=none, 1=mild, 2=moderate, and 3=severe) decreased from 1.49 at baseline to 0.54 after treatment with ENTOCORT EC and 1.64 at baseline to 0.38 after 8 weeks of treatment with prednisolone.

Use of ENTOCORT EC in this age group is supported by evidence from adequate and well-controlled studies of ENTOCORT EC in adults, and by safety and pharmacokinetic studies performed in pediatric patients.

Maintenance Of Clinical Remission Of Mild To Moderate Crohn’s Disease

The efficacy 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% versus 45% for placebo).

Patient's Instructions For Use

Please read this leaflet carefully before you start to take your medicine. It provides a summary of information on your medicine. Following these instructions helps to ensure that you are inhaling the medication correctly.

FOR FURTHER INFORMATION ASK YOUR DOCTOR OR PHARMACIST.

WHAT YOU SHOULD KNOW ABOUT PULMICORT TURBUHALER (budesonide)

Your doctor has prescribed PULMICORT TURBUHALER 200 mcg. It contains a medication called budesonide, which is a synthetic corticosteroid. Corticosteroids are natural substances found in the body that help fight inflammation. They are used to treat asthma because they reduce the swelling and irritation in the walls of the small air passages in the lungs and ease breathing problems. When inhaled regularly, corticosteroids also help to prevent attacks of asthma.

PULMICORT TURBUHALER (budesonide) treats the inflammation—the “quiet part” of asthma that you cannot hear, see, or feel. When inflammation is left untreated, your asthma symptoms and attacks can increase. PULMICORT TURBUHALER (budesonide) works to prevent and reduce your asthma symptoms and attacks.

IMPORTANT POINTS TO REMEMBER ABOUT PULMICORT TURBUHALER (budesonide)

MAKE SURE that this medicine is suitable for you (see “BEFORE USING YOUR PULMICORT TURBUHALER (budesonide) ”).

It is important that you inhale each dose as your doctor has advised.

Use your Turbuhaler as directed by your doctor. DO NOT STOP TREATMENT OR REDUCE YOUR DOSE EVEN IF YOU FEEL BETTER, unless told to do so by your doctor.

DO NOT inhale more doses or use your Turbuhaler more often than instructed by your doctor.

This medicine is NOT intended to provide rapid relief of your breathing difficulties during an asthma attack. It must be taken at regular intervals as recommended by your doctor, and not as an emergency measure.

Your doctor may prescribe additional medication (such as bronchodilators) for emergency relief if an acute

If you also use another medicine by inhalation, you should consult your doctor for instructions on when to use it in relation to using your PULMICORT TURBUHALER (budesonide) .

BEFORE USING YOUR PULMICORT TURBUHALER (budesonide)

TELL YOUR DOCTOR BEFORE STARTING TO TAKE THIS MEDICINE IF YOU:

• are pregnant (or intending to become pregnant),
• are breast-feeding a baby,
• are allergic to budesonide or any other orally inhaled corticosteroid,
• have any infections,
• have or had tuberculosis,
• have osteoporosis,
• have recently been around anyone with chicken pox or measles,
• are planning to have surgery,
• have been taking an oral corticosteroid medicine like prednisone. You may have to follow specific instructions to avoid health risks associated with stopping the use of these types of medicines.

In some circumstances, this medicine may not be suitable and your doctor may wish to prescribe a different medicine. Make sure that your doctor knows what other medicines you are taking including prescription and non-prescription medicines, as well as any vitamins or dietary and herbal supplements.

WHAT ARE THE POSSIBLE SIDE EFFECTS OF PULMICORT TURBUHALER (budesonide) ?

As with all inhaled corticosteroids, you should be aware of the following side effects:

• Increased wheezing right after taking PULMICORT TURBUHALER (budesonide) . Always have a short-acting bronchodilator medicine with you to treat sudden wheezing. Short-acting bronchodilator medicines help to relax the muscles around the airways in your lungs. Wheezing happens when the muscles around the airways tighten. This makes it hard to breathe. In severe cases, wheezing can stop your breathing and cause death if not treated right away.
• Immune system effects and a higher chance of infections.
• Eye problems including glaucoma and cataracts. Eye examinations should be considered while using PULMICORT TURBUHALER (budesonide) .
• A child's growth should be checked regularly while taking PULMICOR TURBUHALER because of the potential for slowed growth.

Based on clinical trials, the most common side effects reported by patients using PULMICORT TURBUHALER (budesonide) are:

• respiratory infection
• headache
• flu symptoms
• sore throat
• sinusitis

These are not all of the possible side effects of PULMICORT TURBUHALER (budesonide) . For more information, ask your doctor, healthcare professional, or pharmacist.

USING YOUR PULMICORT TURBUHALER (budesonide)

• Follow the instructions shown in the section “HOW TO USE YOUR PULMICORT TURBUHALER”. If you have any problems, tell your doctor or pharmacist.
• It is important that you inhale each dose as directed by your doctor. The pharmacy label will usually tell you what dose to take and how often. If it doesn't, or you are not sure, ask your doctor or pharmacist.

DOSAGE

• Use as directed by your doctor.
• It is VERY IMPORTANT that you follow your doctor's instructions as to how many inhalations to take and how often to use your PULMICORT TURBUHALER (budesonide) .
• DO NOT inhale more doses or use your PULMICORT TURBUHALER (budesonide) more often than your doctor advises.
• It may take 1 to 2 weeks or longer before you feel maximum improvement, so IT IS VERY IMPORTANT THAT YOU USE PULMICORT TURBUHALER (budesonide) REGULARLY. DO NOT STOP TREATMENT OR REDUCE YOUR DOSE EVEN IF YOU ARE FEELING BETTER, unless told to do so by your doctor.
• If you miss a dose, just take your regularly scheduled next dose when it is due. DO NOT DOUBLE the dose.

HOW TO USE YOUR PULMICORT TURBUHALER (budesonide)

Read the complete instructions carefully and use only as directed.

PRIMING INSTRUCTIONS:

Before you use a new PULMICORT TURBUHALER (budesonide) for the first time, you should prime it. To do this, turn the cover and lift off. Hold PULMICORT TURBUHALER (budesonide) upright (with mouthpiece up), then twist the brown grip fully to the right and back again to the left. Repeat. Now you are ready to take your first dose (see instructions for “TAKING A DOSE”). You do not have to prime it any other time after this, even if you put it aside for a prolonged period of time.

TAKING A DOSE:

LOADING A DOSE

• Twist the cover and lift off.
• In order to provide the correct dose, PULMICORT TURBUHALER (budesonide) must be held in the upright position (mouthpiece up) whenever a dose of medication is being loaded.
• Twist the brown grip fully to the right as far as it will go. Twist it back again fully to the left.
• You will hear a click.

INHALING THE DOSE

• When you are inhaling, PULMICORT TURBUHALER (budesonide) must be held in the upright (mouthpiece up) or horizontal position.
• Turn your head away from the inhaler and breathe out. Do not shake the inhaler after loading it.
• Place the mouthpiece between your lips and inhale deeply and forcefully. You may not taste or feel the medication.
• Do not chew or bite on the mouthpiece.
• Remove the inhaler from your mouth and exhale. Do not blow or exhale into the mouthpiece.
• If more than one dose is required, just repeat the steps above.
• When you are finished, place the cover back on the inhaler and twist shut. Rinse your mouth with water. Do not swallow.
• Keep your PULMICORT TURBUHALER (budesonide) clean and dry at all times.
• Do not use PULMICORT TURBUHALER (budesonide) if it has been damaged or if the mouthpiece has become detached.

STORING YOUR PULMICORT TURBUHALER (budesonide)

• After each use, place the white cover back on and twist it firmly into place.
• Keep PULMICORT TURBUHALER (budesonide) in a dry place at controlled room temperature, 68-77°F (20-25°C).
• Keep your PULMICORT TURBUHALER (budesonide) in a secure place out of the reach of young children.
• DO NOT use after the date shown on the body of your Turbuhaler.

HOW TO KNOW WHEN YOUR PULMICORT TURBUHALER (budesonide) IS EMPTY

The label on the box or cover will tell you how many doses are in your PULMICORT TURBUHALER. Your PULMICORT TURBUHALER (budesonide) has a convenient dose indicator window just below the mouthpiece.

• When a red mark appears at the top of the window, there are 20 doses of medicine remaining. Now is the time to get your next PULMICORT TURBUHALER (budesonide) .
• When the red mark reaches the bottom of the window, your inhaler should be discarded as it may no longer deliver the correct amount of medication. (You may still hear a sound if you shake it—this sound is not the medicine. This sound is produced by the drying agent inside the Turbuhaler.)
• Remember, you will get a new inhaler each time you refill your prescription.
• Do not immerse it in water to find out if it is empty. Simply check your dose indicator window.

FURTHER INFORMATION ABOUT PULMICORT TURBUHALER (budesonide)

• PULMICORT TURBUHALER (budesonide) delivers your medicine as a very fine powder. Because of this, you may not taste, smell, or feel any medication entering your lungs when inhaling from PULMICORT TURBUHALER (budesonide) This does not mean that you are not getting your medication.
• PULMICORT TURBUHALER (budesonide) should not be used with a spacer.
• PULMICORT TURBUHALER contains only budesonide and does not contain any inactive ingredients.
• PULMICORT TURBUHALER (budesonide) is specially designed to deliver only one dose at a time, no matter how often you click the brown grip. If you accidentally blow into your inhaler after loading a dose, simply follow the instructions for loading a new dose.

This leaflet does not contain the complete information about your medicine. If you have any questions, or are not sure about something, then you should ask your doctor or pharmacist.

You may want to read this leaflet again. Please DO NOT THROW IT AWAY until you have finished your medicine.

REMEMBER: This medicine has been prescribed for you by your doctor. DO NOT give this medicine to anyone else.

USE THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE BY YOUR DOCTOR.

If you have further questions about the use of PULMICORT TURBUHALER (budesonide) , call: 1-800-236-9933.

RHINOCORT AQUA (budesonide) ®
(RINE-o-cort AH-kwa)
(budesonide) Nasal Spray

For use in your nose only

Read the Patient Information that comes with RHINOCORT AQUA (budesonide) Nasal Spray before you start using 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 treatment. If you have questions about RHINOCORT AQUA (budesonide) Nasal Spray, ask your healthcare provider or pharmacist.

What is RHINOCORT AQUA (budesonide) Nasal Spray?

RHINOCORT AQUA (budesonide) Nasal Spray is a prescription medicine used to treat seasonal and year-round allergy symptoms in adults and children 6 years of age and older.

RHINOCORT AQUA Nasal Spray contains budesonide, which is a man-made (synthetic) corticosteroid. Intranasal corticosteroids are natural hormones found in the body that reduce swelling of the lining of your nose. When you spray RHINOCORT AQUA (budesonide) Nasal Spray into your nose, it helps reduce the nasal symptoms of allergic rhinitis (inflammation of the lining of the nose), such as stuffy nose, runny nose, itching and sneezing.

The safety and effectiveness of RHINOCORT AQUA (budesonide) Nasal Spray has not been shown in children under 6 years of age.

Who should not use RHINOCORT AQUA (budesonide) Nasal Spray?

Do not use RHINOCORT AQUA (budesonide) Nasal Spray:

• if you are allergic to budesonide or any of the ingredients in RHINOCORT AQUA Nasal Spray. See the end of this leaflet for a complete list of the ingredients in RHINOCORT AQUA (budesonide) Nasal Spray.

What should I tell my healthcare provider before using RHINOCORT AQUA (budesonide) Nasal Spray?

Before you use RHINOCORT AQUA (budesonide) Nasal Spray, tell your healthcare provider or pharmacist if you:

• have recently been around anyone with chicken pox or measles
• have liver problems
• have any untreated infections
• have ever had an infection called tuberculosis
• have an eye infection
• have recently had surgery or an injury to your nose
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if RHINOCORT AQUA (budesonide) Nasal Spray will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
• are breastfeeding or plan to breastfeed. RHINOCORT AQUA (budesonide) Nasal Spray can pass into your breast milk. Talk to your doctor about the best way to feed your baby if you take RHINOCORT AQUA (budesonide) Nasal Spray.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

RHINOCORT AQUA (budesonide) Nasal Spray may affect the way other medicines work, and other medicines may affect how RHINOCORT AQUA (budesonide) Nasal Spray works.

Know the medicines you take. Keep a list of your medicines with you to show your healthcare provider and pharmacist when you get a new medicine.

How should I use RHINOCORT AQUA (budesonide) Nasal Spray?

• RHINOCORT AQUA (budesonide) Nasal Spray is for use in your nose only. Do not spray it in your eyes or mouth.
• Use RHINOCORT AQUA (budesonide) Nasal Spray exactly as your healthcare provider tells you to use it.
• It is very important that you use RHINOCORT AQUA (budesonide) Nasal Spray regularly. Do not stop using RHINOCORT AQUA (budesonide) Nasal Spray or change your dose without talking to your healthcare provider, even if you are feeling better.
• Talk to your healthcare provider if your symptoms do not improve after taking RHINOCORT AQUA (budesonide) Nasal Spray for 2 weeks or if your symptoms get worse.
• An adult should help a young child use this medicine.
• See the Patient Instructions for Use at the end of this leaflet for complete information on how to use RHINOCORT AQUA (budesonide) Nasal Spray.

What are the possible side effects of RHINOCORT AQUA (budesonide) Nasal Spray?

RHINOCORT AQUA (budesonide) Nasal Spray may cause serious side effects including:

• hole in the cartilage inside the nose (nasal septal perforation). Tell your healthcare provider if you have a whistling sound from your nose when you breathe.
• slow wound healing. You should not use RHINOCORT AQUA (budesonide) Nasal Spray until your nose has healed if you have a sore in your nose, if you have had surgery on your nose, or if your nose has been injured.
• fungal infection in your nose.
• allergic reactions. Tell your healthcare provider or get medical help right away if you have:
  • skin rash, redness or swelling
  • severe itching
  • swelling of the face, mouth and tongue
• immune system problems that may increase your risk of infections. You are more likely to get infections if you take medicines that weaken your body's ability to fight infections. Avoid contact with people who have contagious diseases such as chicken pox or measles while using RHINOCORT AQUA (budesonide) Nasal Spray. Symptoms of infection may include fever, pain, aches, chills, feeling tired, nausea and vomiting.
• adrenal insufficiency, Adrenal insufficiency is a condition in which the adrenal glands do not make enough steroid hormones. Symptom of adrenal insufficiency may include tiredness, weakness, nausea, vomiting and low blood pressure.
• slowed or delayed growth in children. A child's growth should be checked regularly while using RHINOCORT AQUA (budesonide) Nasal Spray.
• eye problems, such as glaucoma and cataracts. Tell your healthcare provider if you have a change in vision or have a history of increased intraocular pressure, glaucoma, and/or cataracts.

Call your healthcare provider or get medical help right away if you have symptoms of any of the serious side effects listed above.

The most common side effects of RHINOCORT AQUA (budesonide) Nasal Spray include:

• nose bleeds
• sore throat
• breathing difficulties such as wheezing, or chest tightening
• cough
• irritation of your nose

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

These are not all of the possible side effects of RHINOCORT AQUA (budesonide) Nasal Spray. 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 FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

You may report side effects to AstraZeneca at 1-800-236-9933.

What should I know about allergic rhinitis?

"Rhinitis" means inflammation of the lining of the nose. It is sometimes called "hay fever." Allergic rhinitis can be caused by allergies to pollen, animal dander, house dust mite, and mold spores. If you have allergic rhinitis, your nose becomes stuffy, runny, and itchy. You may also sneeze a lot. You may have red, itchy, watery eyes; itchy throat; or blocked, itchy ears.

RHINOCORT AQUA (budesonide) Nasal Spray helps to relieve your nasal symptoms.

If you also have itchy, watery eyes, you should tell your healthcare provider. He or she can prescribe additional medication to treat these symptoms.

How should I store RHINOCORT AQUA (budesonide) Nasal Spray?

• Store RHINOCORT AQUA (budesonide) Nasal Spray at 68°F to 77°F (20°C to 25°C).
• Do not freeze RHINOCORT AQUA (budesonide) Nasal Spray.
• Protect RHINOCORT AQUA (budesonide) Nasal Spray from light.
• Do not use RHINOCORT AQUA (budesonide) Nasal Spray after the labeled number of sprays have been used (does not include priming) or after the expiration date shown on the carton or bottle label.
• Keep the green protective cap on RHINOCORT AQUA (budesonide) Nasal Spray when not in use. (Please see Prior to Use on reverse side).
• Keep RHINOCORT AQUA (budesonide) Nasal Spray and all medications out of the reach of children.

General Information about the safe and effective use of RHINOCORT AQUA (budesonide) Nasal Spray:

Do not use RHINOCORT AQUA (budesonide) Nasal Spray for a condition for which it was not prescribed. Do not give RHINOCORT AQUA (budesonide) Nasal Spray to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Information leaflet summarizes the most important information about RHINOCORT AQUA (budesonide) Nasal Spray. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about RHINOCORT AQUA (budesonide) Nasal Spray that is written for health professionals.

For more information, go to www.astrazeneca-us.com or call AstraZeneca at 1-800-236-9933.

What are the Ingredients of RHINOCORT AQUA (budesonide) Nasal Spray?

Active ingredient: budesonide

Inactive ingredients: Microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose anhydrous, polysorbate 80, disodium edetate, potassium sorbate, and purified water, and hydrochloric acid.

Patient Instructions for Use

For use in your nose only. Do not spray in your eyes or mouth.

Read the Patient Instructions for Use carefully before you start to use RHINOCORT AQUA (budesonide) Nasal Spray. If you have any questions, ask your healthcare provider

Figure A

How to prime your RHINOCORT AQUA (budesonide) Nasal Spray

Before you use RHINOCORT AQUA (budesonide) Nasal Spray, the bottle must be primed. To prime RHINOCORT AQUA (budesonide) Nasal Spray:

1. Pull to remove the green protective cap off the nasal spray unit.

2. Shake the bottle gently for a few seconds before each use.

3. Hold the bottle firmly, as shown in Figure B, with your index and middle finger on either side of the spray tip and your thumb underneath the bottle.

Figure B

4. Activate the pump by quickly and firmly pressing down on the white collar while holding the base of the bottle with your thumb.

5. Before your first use of RHINOCORT AQUA (budesonide) Nasal Spray, shake the bottle gently. The pump must be primed by pressing down on the white collar 8 times. The pump is now ready to use. If used daily the pump does not need to be reprimed. If not used for 2 days in a row, reprime with 1 spray or until a fine spray appears. If not used for more than 14 days, rinse the spray tip of the pump using the cleaning steps listed at the end of this leaflet. After cleaning reprime with 2 sprays or until a fine spray appears.

Each bottle of RHINOCORT AQUA (budesonide) Nasal Spray contains enough medicine for you to spray medicine from the bottle 120 times after the bottle is primed.

You should not use the bottle of RHINOCORT AQUA (budesonide) Nasal Spray after 120 sprays. Additional sprays after 120 may not contain the right amount of medicine. You should keep track of the number of sprays you use from each bottle of RHINOCORT AQUA Nasal Spray and throw away any remaining medicine that may be left in the bottle. Refill your prescription monthly.

How to use your RHINOCORT AQUA (budesonide) Nasal Spray

Follow these instructions for daily use of RHINOCORT AQUA (budesonide) Nasal Spray:

1. Gently blow your nose to clear your nostrils, if necessary.
2. Shake the bottle gently for a few seconds and remove the green protective cap.
3. Hold the bottle firmly with your index and middle finger on either side of the spray tip and your thumb underneath the bottle (See Figure C).

Figure C

4. Insert the spray tip into your nostril (the tip should not reach far into your nose). Close the other nostril with a finger and lean your head slightly forward so the spray will aim toward the back of your nose (See Figure D).

Figure D

5. For each spray, activate the pump by quickly and firmly pressing down on the white collar while holding the base of the bottle with your thumb. Breathe gently inward through the nostril.

6. After spraying into your nostril, lean your head backward for a few seconds (See Figure E).

Figure E

7. If a second spray is needed in the same nostril, repeat steps 3 through 6.

8. Repeat steps 3 through 7 for your other nostril.

9. Avoid blowing your nose for 15 minutes after you use RHINOCORT AQUA (budesonide) Nasal Spray.

10. Wipe the spray tip with a clean tissue (See Figure F), and replace the green protective cap. Store the bottle in an upright position.

Figure F

How to clean your RHINOCORT AQUA (budesonide) Nasal Spray

Figure G

Rinse the green protective cap and the spray tip regularly. To do this:

1. Remove the green protective cap and lift off the spray tip (See Figure G).
2. Wash only the green protective cap and the spray tip in warm water and rinse them in cold tap water.
3. 3. Allow the green protective cap and the spray tip to air-dry completely before reassembling the nasal spray.
4. If the spray tip becomes blocked, it can be cleared by repeating Steps 1 through 3. Do not unblock the nasal applicator with a pin or other sharp object.

For additional information about RHINOCORT AQUA (budesonide) ® Nasal Spray, please call the AstraZeneca Information Center, Monday through Friday, 8 am - 6 pm ET, excluding holidays at 1-800-236-9933.

Oral:

How should I take budesonide extended release tablets?

• Take budesonide extended release tablets exactly as your healthcare provider tells you to take it.
• Your healthcare provider will tell you how many budesonide extended release tablets to take.
• Take budesonide extended release tablets in the morning.
• Take budesonide extended release tablets capsules whole with water. Do not chew, crush, or break budesonide extended release tablets before swallowing.
• If you take too much of budesonide, call your healthcare provider right away or go to the nearest hospital emergency room.

How should I take budesonide capsules?

• Take budesonide capsules exactly as your healthcare provider tells you to take it.
• Take budesonide capsules in the morning. Swallow each budesonide capsule whole. Do not open, chew, or crush budesonide capsules.
• Your provider will tell you how long to take budesonide capsules.

Topical:

• Budesonide nasal spray is for use in your nose only. Do not spray it in your eyes or mouth.
• Use budesonide nasal spray exactly as your healthcare provider tells you to use it.
• It is very important that you use budesonide nasal spray regularly. Do not stop using budesonide nasal spray or change your dose without talking to your healthcare provider, even if you are feeling better.
• Talk to your healthcare provider if your symptoms do not improve after taking budesonide nasal spray for 2 weeks or if your symptoms get worse.
• An adult should help a young child use this medicine.

Inhalation:

• Use budesonide inhalation exactly as prescribed by your healthcare provider. 
• You must use budesonide inhalation regularly for it to work.
• Be sure you know the difference between budesonide inhalation and any other inhaled medicines that are prescribed for you, including what you use them for (prescribed use) and what they look like.
• Do not stop using budesonide inhalation, even if your symptoms get better. Your healthcare provider will change your medicines as needed.
• Do not change or stop any medicines used to control or treat your breathing problems, unless your healthcare provider tells you to.
• Rinse your mouth with water and spit the water out after each dose of budesonide inhalation. Do not swallow the water. This will lessen the chance of getting a fungal infection (thrush) in the mouth.
• If you miss a dose, just take your next regularly scheduled dose when it is due. Do not use budesonide inhalation more often or use more puffs than you have been prescribed.
• Make sure you always have a short-acting beta2-agonist medicine with you. Use your short acting beta2-agonist medicine if you have breathing problems between doses of budesonide inhalation or if a sudden asthma attack happens.

Budesonide is a steroid that reduces inflammation in the body.

Budesonide is used to treat mild to moderate Crohn's disease.

Budesonide may also be used for purposes not listed in this medication guide.

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Take this medicine in the morning with a full glass of water.

Do not crush, chew, or break a budesonide capsule or tablet. Swallow it whole.

Your dosage needs may change if you have surgery, are ill, or are under stress. Do not change your doses or medication schedule without advice from your doctor.

Call your doctor if your symptoms do not improve, or if they get worse while using budesonide.

Budesonide can weaken your immune system. Tell your doctor if you have signs of infection such as fever, chills, body aches, vomiting, or feeling tired.

If you use this medicine long-term, you may need frequent medical tests.

Store at room temperature away from moisture and heat. Keep the bottle tightly closed when not in use.

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• thinning skin, easy bruising, increased acne or facial hair;

• swelling in your ankles;

• weakness, tiredness, or a light-headed feeling, like you might pass out;

• nausea, vomiting, rectal bleeding;

• pain or burning when you urinate;

• menstrual problems (in women), impotence or loss of interest in sex (in men); or

• stretch marks, changes in the shape or location of body fat (especially in your face, neck, back, and waist).

Common side effects may include:

• headache;

• nausea, stomach pain, gas, bloating, constipation;

• feeling tired;

• joint pain;

• acne; or

• cold symptoms such as stuffy nose, sneezing, sore throat.

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Contraindications

• Known hypersensitivity to budesonide or any ingredient in the formulation.1 2 3 g j

• Orally inhaled budesonide for primary treatment of acute asthmatic attacks or status asthmaticus when intensive measures (e.g., an orally inhaled β2-adrenergic agonist, an orally inhaled anticholinergic agent, subcutaneous epinephrine, IV aminophylline, and/or an oral/IV glucocorticoid) are required.2 3 19 27 g j

• When budesonide is used in fixed combination with formoterol fumarate, contraindications associated with formoterol should be considered.41

Warnings/Precautions

Warnings

Long-acting β2-adrenergic agonists, such as formoterol, a component of Symbicort, increase the risk of asthma-related death.41 44 Data from clinical trials suggest that long-acting β2-adrenergic agonists also increase the risk of asthma-related hospitalization in children and adolescents.41 44

Use the fixed combination of budesonide and formoterol only in patients with asthma who have not responded adequately to long-term asthma controller therapy (e.g., inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a long-acting β2-adrenergic agonist.41 44 (See Asthma under Uses.)

Possible life-threatening adrenal insufficiency in patients being switched from systemic corticosteroids to orally inhaled budesonide.2 3 28 j

Withdraw systemic corticosteroid therapy gradually.1 2 3 6 j In general, the greater the dosage and duration of systemic corticosteroid therapy, the greater the time required for withdrawal of systemic corticosteroids and replacement by orally inhaled corticosteroids.14

Monitor carefully for objective signs of adrenal insufficiency (e.g., fatigue, lassitude, weakness, nausea, vomiting, hypotension) and asthma instability (e.g., airway function) during withdrawal of systemic therapy.1 j Carefully monitor lung function (forced expiratory volume in 1 second [FEV1], morning peak expiratory flow [PEF]), adjunctive β2-adrenergic agonist use, and asthma symptoms.j Patients who have been maintained on ≥20 mg of prednisone (or its equivalent) daily may be most susceptible to such adverse events, particularly during latter part of the transfer.2 3 j (See Conversion to Orally Inhaled Therapy in Patients Receiving Systemic Corticosteroids under Dosage and Administration.)

Corticosteroid withdrawal symptoms (e.g., joint pain, muscular pain, lassitude, depression) may occur.1 2 3 g j

Adrenal insufficiency may occur during exposure to trauma, surgery, infection (particularly gastroenteritis), or other conditions associated with acute electrolyte loss.1 2 3 j

Possible unmasking of allergic conditions previously controlled by systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).1 2 3 6 j

Do not use the fixed combination of budesonide and formoterol fumarate dihydrate for transferring therapy from systemic to inhaled corticosteroids.g

Increased susceptibility to infections in patients taking immunosuppressant drugs compared with healthy individuals.1 2 3 g j Certain infections (e.g., varicella [chickenpox], measles) can have a more serious or even fatal outcome in such patients, particularly in children.1 2 3 g

Take particular care to avoid exposure in susceptible patients.1 2 3 e g j If exposure to varicella or measles occurs in susceptible patients, consider administering varicella zoster immune globulin (VZIG) or pooled immune globulin (IG), respectively.1 2 3 28 e g j Consider treatment with an antiviral agent if varicella develops.1 2 3 e g j

Possible life-threatening, acute, paradoxical bronchospasm and/or wheezing.2 3 g j If bronchospasm occurs, treat immediately with a short-acting bronchodilator, discontinue treatment with budesonide, and institute alternative therapy.2 3 28 g j

General Precautions

Glaucoma, increased IOP, and cataracts reported rarely in patients receiving orally inhaled corticosteroids.2 3 g h j

Use delayed-release capsules with caution in patients with glaucoma, cataracts, or a family history of glaucoma.1 6

Consider regular eye examinations.h j

Administration of higher than recommended dosages of orally inhaled budesonide or prolonged oral administration of budesonide capsules may result in manifestations of hypercorticism and suppression of HPA function.1 2 3 g j To minimize potential for such changes, do not exceed recommended dosages of orally inhaled budesonide-containing therapy.a g j

Monitor patients receiving orally inhaled budesonide-containing therapy for any evidence of systemic corticosteroid effects.a g If systemic corticosteroid effects occur, reduce the dosage of budesonide-containing therapy slowly, consistent with accepted procedures for reducing corticosteroid dosage and management of asthma symptoms.a g j

Take particular care in monitoring patients postoperatively or during periods of stress for evidence of inadequate adrenal response.a g j Supplemental therapy with a systemic corticosteroid required during stress or severe asthma attacks.1 a g

Long-term use may affect normal bone metabolism, resulting in a loss of bone mineral density (BMD).g

Use of orally inhaled corticosteroids can pose additional risks in patients with major risk factors for decreased BMD, such as tobacco use, advanced age, sedentary lifestyle, poor nutrition, family history of osteoporosis, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, additional corticosteroids).g h

Use delayed-release capsules with caution in patients with osteoporosis.1 6

Possible growth suppression in pediatric patients.2 3 g j (See Pediatric Use under Cautions.)

Use delayed-release capsules with caution in patients with hypertension, diabetes mellitus, peptic ulcer, a family history of diabetes, or any other condition in which glucocorticoids may be associated with adverse effects.1 6

Localized candidal infections of the mouth and/or pharynx reported with oral inhalation therapy.2 3 g j

If infection occurs, initiate appropriate local or systemic antifungal treatment while still continuing with inhaled budesonide therapy.2 3 g j May require discontinuance of budesonide therapy (under close medical supervision) in some patients.2 3 g j

Lower respiratory tract infections, including pneumonia, reported with orally inhaled corticosteroid therapy.g Use oral inhalation therapy with extreme caution, if at all, in patients with clinical tuberculosis or latent M. tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.2 3 g j

Use delayed-release capsules with caution in patients with tuberculosis.1 6

Unknown long-term local and systemic effects of the drug in humans, particularly local effects on developmental or immunologic processes in the mouth, pharynx, trachea, and lung.2 g j

When used in fixed combination with formoterol fumarate dihydrate, consider the cautions, precautions, and contraindications associated with formoterol.41

Specific Populations

Category B (orally inhaled powder and inhalation suspension); category C (oral capsules, inhalation aerosol).1 2 3 28 g j

Hypoadrenalism may occur in infants of women receiving corticosteroid therapy during pregnancy; monitor these infants carefully.1 2 3 g j

Distributed into milk.g j

Use of oral capsules, oral inhalation aerosol, or oral inhalation powder (Pulmicort Turbuhaler) not recommended; discontinue nursing or the drug.1 3 g Caution advised if inhalation suspension is used.f

Use oral inhalation powder (Pulmicort Flexhaler) only if clinically appropriate; titrate to lowest effective dosage and use inhaler immediately after nursing to minimize infant exposure.j

Safety and efficacy of oral budesonide delayed-release capsules not established in pediatric patients <18 years of age with Crohn’s disease.1 28

Safety and efficacy of budesonide inhalation powder not established in children <6 years of age.3 j

Efficacy of budesonide inhalation suspension not established in children <1 year of age,2 while safety of the suspension not evaluated in children <6 months of age.2

Efficacy of inhalation aerosol containing budesonide in fixed combination with formoterol fumarate dihydrate not established in children <12 years of age.g Safety of combination therapy in children 6 to <12 years of age similar to that in adolescents and adults.g

With long-term use, slows growth rate in children and adolescents.2 3 g j Monitor routinely (e.g., via stadiometry) growth and development of pediatric patients receiving orally inhaled corticosteroid therapy.2 3 g j Weigh benefits of orally inhaled corticosteroid therapy versus possibility of growth suppression and the risks associated with alternative therapies.a g Use the lowest possible dosage that effectively controls asthma.35 a g

Insufficient experience with oral drug in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.1 6 (See Geriatric Patients under Dosage and Administration.)

Safety and efficacy of inhalation powder, inhalation suspension, or inhalation aerosol in patients ≥65 years of age similar to that in younger adults.2 3 6 28 g

Monitor patients with Crohn’s disease and moderate to severe hepatic impairment for increased signs and symptoms of hypercorticism.1 6 (See Hepatic Impairment under Dosage and Administration.)

Common Adverse Effects

With oral capsules, headache,1 6 7 40 dizziness,1 nausea,1 6 7 11 40 vomiting,1 6 7 11 40 dyspepsia,1 6 11 40 diarrhea,1 40 sinusitis,1 40 symptoms of hypercorticism,1 respiratory infection,1 6 40 viral infection,1 40 pain (including back pain),1 40 arthralgia,1 40 fatigue.1 6 40 Adverse effect profile in long-term treatment similar to short-term treatment.1

With oral inhalation, respiratory infection,2 3 pharyngitis,3 rhinitis,2 3 sinusitis, 3 cough,2 3 otitis (media or externa),2 flu-like syndrome,2 headache,3 pain (e.g., back pain).3

In the U.S.

• Entocort EC
• Uceris

In Canada

• Pulmicort
• Pulmicort Spacer

Available Dosage Forms:

• Capsule, Delayed Release
• Tablet, Extended Release
• Capsule, Extended Release

Therapeutic Class: Endocrine-Metabolic Agent

Pharmacologic Class: Adrenal Glucocorticoid

It is very important that your doctor check your progress at regular visits for any problems or unwanted effects that may be caused by budesonide.

If your condition does not improve or if it become worse, check with your doctor.

budesonide may cause serious allergic reactions, including anaphylaxis. Anaphylaxis requires immediate medical attention. The most serious signs of this reaction are very fast or irregular breathing, gasping for breath, or fainting. Other signs may include changes in color of the skin of the face, very fast but irregular heartbeat or pulse, hive-like swellings on the skin, and puffiness or swellings of the eyelids or around the eyes. If these side effects occur, get emergency help at once.

Using too much of budesonide or using it for a long time may increase your risk of having adrenal gland problems. Talk to your doctor if you have more than one of these symptoms while you are using budesonide: darkening of the skin, diarrhea, dizziness, fainting, loss of appetite, mental depression, nausea, skin rash, unusual tiredness or weakness, or vomiting.

If you are taking another steroid medicine and will switch to Uceris™, check first with your doctor. This may increase your chance of having steroid withdrawal side effects, such as headache, loss of appetite, blurred vision, change in the ability to see colors (especially blue or yellow), or vomiting.

You may get infections more easily while using budesonide. Avoid people who are sick or have infections. Tell your doctor right away if you have been exposed to someone with chickenpox or measles.

Make sure any doctor or dentist who treats you knows that you are using budesonide. You may need to stop using budesonide several days before having surgery or medical tests.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Bruising easily
• chills
• colds
• cough or hoarseness
• fever
• flu-like symptoms
• sneezing
• sore throat

• Abdominal or stomach pain
• bladder pain
• bleeding after defecation
• bloody or cloudy urine
• blurred vision
• burning while urinating
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• chest pain
• convulsions
• cough producing mucus
• decreased urine
• diarrhea
• difficult or labored breathing
• difficult or painful urination
• dizziness
• dry mouth
• eye pain
• fast, irregular, pounding, or racing heartbeat or pulse
• feeling of warmth
• general feeling of discomfort or illness
• headache
• heartburn
• increase in body movements
• increased thirst
• increased urge to urinate during the night
• irregular heartbeat
• joint pain
• loss of appetite
• lower back or side pain
• mood changes
• muscle aches and pains
• nausea or vomiting
• nervousness
• numbness or tingling in the hands, feet, or lips
• pain or discomfort in the chest, upper stomach, or throat
• pounding in the ears
• rectal bleeding
• redness of the face, neck, arms, and occasionally, upper chest
• runny nose
• severe constipation
• shakiness in the legs, arms, hands, or feet
• shivering
• slow or fast heartbeat
• stomach cramps
• sweating
• swelling of the legs and feet
• swelling or puffiness of the face
• tightness in the chest
• trouble sleeping
• uncomfortable swelling around the anus
• unusual tiredness or weakness
• upper abdominal or stomach pain
• waking to urinate at night
• weight gain
• weight loss

• Bulging soft spot on the head of an infant
• change in the ability to see colors, especially blue or yellow
• difficulty with swallowing
• hives, itching, or skin rash
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• belching
• blemishes on the skin
• heartburn
• indigestion
• pain or tenderness around the eyes and cheekbones
• pimples
• rounded or moon face
• stomach discomfort, upset, or pain
• stuffy nose

• Accumulation of pus
• agitation
• blistering, crusting, irritation, itching, or reddening of the skin
• bloated or full feeling
• change in hearing
• changes in vision
• cracked, dry, or scaly skin
• cracks in the skin at the corners of mouth
• difficulty having a bowel movement (stool)
• difficulty with moving
• dizziness or lightheadedness
• ear drainage
• earache or pain in the ear
• excess air or gas in the stomach or intestines
• feeling of constant movement of self or surroundings
• hair loss or thinning of the hair
• increased appetite
• increased hair growth, especially on the face
• lack or loss of strength
• loss of memory
• muscle pains or stiffness
• nervousness
• pain, swelling, or redness in the joints
• passing gas
• pinpoint red or purple spots on the skin
• pressure in the stomach
• problems with memory
• redness, swelling, or soreness of the tongue
• sensation of spinning
• skin rash
• skin rash, encrusted, scaly, and oozing
• sleepiness or unusual drowsiness
• soreness or redness around the fingernails and toenails
• swelling of the abdominal or stomach area
• swollen joints
• uterine bleeding between menstrual periods

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

You should not take this medication if you are allergic to budesonide, or if you have active tuberculosis or any other type of a serious bacterial, viral, or fungal infection.

Before taking budesonide, tell your doctor if you are allergic to any drugs, or if you have:

• kidney disease;
• liver disease (including cirrhosis);
• stomach ulcer, intestinal bleeding or blockage;
• measles, scarlet fever, or any other condition with a skin rash;
• diverticulitis;
• osteoporosis;
• high blood pressure;
• heart disease or coronary artery disease;
• overactive thyroid;
• mental illness;
• a muscle disorder called myasthenia gravis; or
• a personal or family history of diabetes, glaucoma, or cataract.

FDA Pregnancy Category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

Budesonide can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Before using budesonide, tell your doctor if you have been sick or had an infection of any kind. Also tell your doctor if you have liver disease, glaucoma or cataracts, herpes simplex infection of your eyes, tuberculosis, sores or ulcers in your nose, or if you have recently had injury of or surgery on your nose.

It may take up to 2 weeks of using this medicine before your symptoms improve. For best results, keep using the medication as directed. Talk with your doctor if your symptoms do not improve after a week of treatment.

To be sure this medication is not causing harmful effects on your nose or sinuses, your doctor may want to check your progress on a regular basis. Do not miss any scheduled visits to your doctor.

Budesonide nasal can lower the blood cells that help your body fight infections. Avoid being near people who are sick or have infections. Call your doctor for preventive treatment if you are exposed to chicken pox or measles. These conditions can be serious or even fatal in people who are using budesonide nasal.

Avoid getting this medication in your eyes. If this does happen, rinse with water and call your doctor.

Steroid medicines can affect growth in children. Talk with your doctor if you think your child is not growing at a normal rate while using budesonide nasal.

• Allergy (Allergies)
• Allergy Drugs: Prescription and OTC
• Chronic Rhinitis and Post-Nasal Drip
• Hay Fever (Allergic Rhinitis)

Enteric coated capsules
Initial dose: 9 mg orally once a day in the morning for up to 8 weeks
-May repeat course for recurring episodes of active disease

Comments:
-Patients with mild to moderate active Crohn's disease involving the ileum and/or ascending colon have been switched from oral prednisolone to this drug with no reported episodes of adrenal insufficiency; prednisolone should be tapered while initiating therapy with this drug.
-Capsules should be swallowed whole; avoid grapefruit juice for the duration of therapy.
-Once patients symptoms are controlled (Crohn's Disease Activity Index [CDAI] less than 150); maintenance dosing should be started.

Use: Treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon.

Inhalation Suspension (administer via jet nebulizer):
Age: 1 to 8 years: Initial and maximum dose are based on prior asthma therapy:
-Previously treated with bronchodilators alone: 0.5 mg via oral inhalation once a day or 0.25 mg via oral inhalation twice a day; Maximum daily dose: 0.5 mg
-Previously treated with inhaled corticosteroids: 0.5 mg once a day or 0.25 mg twice a day; may increase up to 0.5 mg twice a day; Maximum daily dose: 1 mg
-Previously treated with oral corticosteroids: 1 mg once a day or 0.5 mg twice a day; Maximum daily dose: 1 mg

Comment: For symptomatic patients who do not respond to non-steroid therapy, an initial inhalation suspension dose of 0.25 mg once a day may be considered.

FLEXHALER(R) Inhalation Powder (oral inhaler):
Age: 6 to 12 years:
-Initial dose: 180 mcg via oral inhalation twice a day; some patients may require an initial dose of 360 mcg twice a day
-Maintenance dose: May increase dose after 1 to 2 weeks if response is not adequate; once asthma stability has been achieved, titrate to the lowest effective dose to reduce the possibility of side effects
-Maximum dose: 360 mcg twice a day

TURBUHALER(R) Inhalation Powder (oral inhaler):
Age 6 to 12 years:
-Initial dose: 100 to 200 mcg via oral inhalation twice a day
Maintenance dose: Lowest dose that keeps patient symptom-free

TURBUHALER(R) Inhalation Powder (oral inhaler):
Age: Over 12 years:
Initial dose: 400 to 2400 mcg via oral inhalation daily in divided doses
Maintenance dose: 200 to 400 mcg via oral inhalation twice a day; higher doses may be necessary for longer or shorter periods of time in some patients; after asthma stability has been achieved, titrate to the lowest effective dose to reduce the possibility of side effects
-Once daily dosing may be considered in patients requiring 400 mcg per day; dose should be given in the evening

Comments:
-Improvement in asthma control can occur as early as 24 hours; maximum benefit is usually achieved within 1 to 2 weeks; individual patients may experience a variable onset and degree of symptom relief.
-If asthma symptoms arise between doses, a fast acting inhaled bronchodilator should be used for immediate relief; this drug should not be used for the relief of acute bronchospasm.
-Once daily dosing may be used unless it does not provide adequate control, then dosing should be administered as a divided dose, adjusting dose as needed.
-Once asthma stability has been achieved, titrate to the lowest effective dose to reduce the possibility of side effects.

Use: For the maintenance treatment of asthma as prophylactic therapy.