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Budesonide

Pronunciation

Class: Adrenals
VA Class: NT200
Chemical Name: [11β,16α(R)]-16,17-Butylidene-bis(oxy)-11,21-dihydroxy-pregna-1,4-diene-3,20-dione and 16α,17-[(S)-butylidinebis(oxy)]-11β,21-dihydroxypregna-1,4-diene-3,20-dione
Molecular Formula: C25H34O6
CAS Number: 51333-22-3
Brands: Entocort EC, Pulmicort, Symbicort

Warning(s)

Special Alerts:

[Posted 02/18/2010] FDA notified healthcare professionals and consumers that, due to safety concerns, FDA is requiring a risk management strategy (REMS) and class-labeling changes for all Long-Acting Beta-Agonists (LABAs). The REMS will require a revised Medication Guide written specifically for patients, and a plan to educate healthcare professionals about the appropriate use of LABAs. These changes are based on FDA’s analyses of studies showing an increased risk of severe exacerbation of asthma symptoms, leading to hospitalizations in pediatric and adult patients as well as death in some patients using LABAs for the treatment of asthma.

Healthcare professionals are reminded that to ensure the safe use of these products:

  • Single-ingredient LABAs should only be used in combination with an asthma controller medication; they should not be used alone.

  • LABAs should only be used long-term in patients whose asthma cannot be adequately controlled on asthma controller medications.

  • LABAs should be used for the shortest duration of time required to achieve control of asthma symptoms and discontinued, if possible, once asthma control is achieved. Patients should then be maintained on an asthma controller medication.

  • Pediatric and adolescent patients who require the addition of a LABA to an inhaled corticosteroid should use a combination product containing both an inhaled corticosteroid and a LABA, to ensure compliance with both medications.

FDA has determined that the benefits of LABAs in improving asthma symptoms outweigh the potential risks when used appropriately with an asthma controller medication in patients who need the addition of LABAs. FDA believes the safety measures recommended will improve the safe use of these drugs. For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for budesonide to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of budesonide and consists of the following: communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Synthetic, non-halogenated corticosteroid; potent glucocorticoid and weak mineralocorticoid activity.1 2 3 6 31 j

Uses for Budesonide

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Crohn’s Disease

Used orally for the management of an active episode of mild-to-moderate Crohn’s disease involving the ileum and/or ascending colon1 4 5 6 7 8 9 10 11 12 13 15 16 17 18 31 and for maintenance of clinical remission for up to 3 months in this condition.1 40

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Has been used for the management of mild to moderately active Crohn’s disease in a limited number of children 9.5–18 years of age.10

Asthma

Long-term prevention of bronchospasm in patients with asthma.3 28 j

In corticosteroid-dependent patients, may permit a substantial reduction in daily maintenance dosage of systemic corticosteroid and gradual discontinuance of corticosteroid maintenance dosages.2 3 28 j

Used in fixed combination with formoterol in asthmatic patients whose disease is inadequately controlled with other anti-asthma therapy (e.g., low-to-medium dosages of inhaled corticosteroids) or whose disease severity warrants treatment with 2 maintenance therapies.g

Fixed combination with formoterol should not be used in patients whose asthma can be successfully managed with inhaled corticosteroids and occasional use of inhaled short-acting β2-adrenergic agonists.g

Not indicated for management of acute bronchospasm.2 3 g j

Not indicated for treatment or prevention of exercise-induced bronchospasm.g

Budesonide Dosage and Administration

General

Asthma

  • Individualize dosage carefully according to disease severity.j

  • Base initial and maximum dosages of oral inhalation on previous asthma therapy.2 3

  • After a satisfactory response is obtained, decrease dosage gradually to the lowest dosage that maintains an adequate clinical response.2 3 j Achieve the lowest effective dosage, particularly in children, since inhaled corticosteroids have the potential to affect growth.g j (See Pediatric Use under Cautions.)

Conversion to Orally Inhaled Therapy in Patients Receiving Systemic Corticosteroids

  • When switching from systemic corticosteroids to orally inhaled budesonide, asthma should be reasonably stable before initiating withdrawal from systemic corticosteroids.j

  • Initially, administer the oral inhalation therapy concurrently with the maintenance dosage of the systemic corticosteroid.2 a j After about 1 week, gradually withdraw systemic corticosteroid, followed by further reductions after an interval of 1 or 2 weeks.2 3 j

  • Usual decrements of ≤2.5 mg or ≤25% of prednisone dosage (or its equivalent) every 1–2 weeks used in patients receiving budesonide powder for inhalation or inhalation suspension, respectively.2 3 j Once oral corticosteroids are discontinued and symptoms of asthma have been controlled, titrate the dosage to the lowest effective level.2 3 g

  • Death has occurred in some individuals due to adrenal insufficiency in whom systemic corticosteroids were withdrawn too rapidly.j If evidence of adrenal insufficiency occurs, increase systemic corticosteroid dosage temporarily and then continue withdrawal from systemic corticosteroids more slowly.j (See Withdrawal of Systemic Corticosteroid Therapy under Cautions.)

Administration

Administer orally as delayed-release capsules.1 6 7 9 11 12 15 31

Administer by oral inhalation via nebulization (Pulmicort Respules),2 d an oral aerosol inhaler (Symbicort), or an oral powder inhaler (Pulmicort Flexhaler, Pulmicort Turbuhaler).3 28 g j

Oral Administration

Administer orally once daily as delayed-release capsules containing enteric-coated granules.1 6 28 31

Swallow the capsules intact; do not chew or break.1 6 However, limited data indicate that the release characteristics of capsules were not affected when unencapsulated granules were added to applesauce for 30 minutes.28

Avoid concomitant use of the capsules and grapefruit juice.1 6 (See Specific Drugs or Food under Interactions.)

Manufacturer makes no specific recommendations regarding administration with meals;1 a high-fat meal may decrease the rate of absorption.1 6 (See Absorption under Pharmacokinetics.)

Oral Inhalation

Following each dose, rinse the mouth with water to remove residual drug and to minimize the development of fungal overgrowth and/or infection.2 3 24 25 28 g h

Inhalation Powder

Prime the oral inhaler prior to initial use.3 25 j k

Do not shake Pulmicort Flexhaler.j

Actuate inhaler and inhale deeply and forcefully.3 25 j k

Pulmicort Turbuhaler and Pulmicort Flexhaler cannot be refilled; discard when empty.3 25 j k

Inhalation Suspension

Do not administer the oral inhalation suspension parenterally or use with ultrasonic nebulizers.2 24 28

Using in vitro testing at a flow rate of 5.5 L per minute for an average of 5 minutes, the Pari-LC-Jet Plus nebulizer delivered at the mouthpiece approximately 17% of the original dose.f

Administer using a jet nebulizer (with face mask or mouthpiece) connected to a compressor that has an adequate air flow.2 28 To optimize delivery and to avoid exposure of the eyes to nebulized drug, adjust the face mask properly.2 24

When a face mask is used for nebulization, wash the face after each use to avoid dermatologic corticosteroid effects (e.g., rash, contact dermatitis).2 28

Safety and efficacy of budesonide inhalation suspension administered by a nebulizer other than the Pari-LC-Jet Plus Nebulizer or a compressor other than the Pari Master compressor not established.2 28

Inhalation Aerosol

Administer budesonide in fixed combination with formoterol using an aerosol inhaler device.g Administer twice daily (morning and evening).g h

Test spray 2 times before first use, if not used for >7 days, or if dropped.g h

Shake well for 5 seconds immediately prior to use.g h

Clean inhaler every 7 days by wiping mouthpiece with a dry cloth.g h

Use the actuator supplied with the product to administer budesonide in fixed combination with formoterol.g h

Symbicort cannot be refilled; discard when empty.h

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Dosage of budesonide inhalation powder is expressed in mcg delivered from the mouthpiece.a j The amount of drug powder delivered to the lungs depends on factors such as the patient’s inspiratory flow.3 28 j

Each actuation of the Pulmicort Turbuhaler inhaler contains 200 mcg of budesonide inhalation powder and delivers approximately 160 mcg of budesonide per activation from the mouthpiece.3

Each actuation of the Pulmicort Flexhaler inhaler contains 90 or 180 mcg of budesonide inhalation powder and delivers approximately 80 or 160 mcg of budesonide, respectively, per activation from the mouthpiece.j

When switching between Pulmicort Turbuhaler and Pulmicort Flexhaler, dose may vary and is not predictable by dose of other inhaler.j Follow dosage recommendations; titrate based on clinical response.j

Delivery of oral inhalation suspension (Pulmicort Respules) to the lungs depends on the type of jet nebulizers used, performance of the compressor, and on factors such as the patient’s inspiratory flow.2 28

Dosage of budesonide in fixed combination with formoterol fumarate dihydrate (Symbicort) inhalation aerosol is expressed in mcg delivered from the mouthpiece.g Each actuation of the Symbicort inhalation aerosol delivers 91 or 181 mcg of budesonide and 5.1 mcg of formoterol fumarate dihydrate from the valve, and 80 or 160 mcg of budesonide and 4.5 mcg of formoterol fumarate dihydrate from the actuator per metered spray.g The amount of drug delivered to the lungs depends on factors such as the patient’s inspiratory flow.g The aerosol inhaler delivers 60 metered sprays per 6- or 6.9-g canister, and 120 metered sprays per 10.2-g canister.g

Pediatric Patients

Asthma
Maintenance Monotherapy
Oral Inhalation Powder (Pulmicort Turbuhaler)

Children ≥6 years of age previously receiving bronchodilators alone: Initially, 160 mcg (labeled 200 mcg) twice daily.3 28 a If required, may increase dosage to a maximum of 320 mcg (labeled 400 mcg) twice daily.3 28 a

Children ≥6 years of age previously receiving inhaled corticosteroids: Initially, 160 mcg (labeled 200 mcg) twice daily.3 28 a If required, may increase dosage to a maximum of 320 mcg (labeled 400 mcg) twice daily.3 28 a

In children with mild-to-moderate asthma whose asthma is adequately controlled with inhaled corticosteroids, consider 160 or 320 mcg (labeled 200 or 400 mcg, respectively) once daily.3 a

Oral Inhalation Powder (Pulmicort Flexhaler)

Children and adolescents 6–17 years of age: Initially, 160 mcg (labeled 180 mcg) twice daily.j If required, may increase dosage to a maximum of 320 mcg (labeled 360 mcg) twice daily.j In some patients, an initial dosage of 320 mcg (labeled 360 mcg) twice daily may be appropriate.j

Oral Inhalation Suspension

Children 1–8 years of age inadequately controlled with nonsteroidal (e.g., bronchodilator, mast-cell stabilizer) therapy: Initially, 0.25 mg once daily.2 28 If the response is inadequate, increase the total daily dosage and/or administer in divided doses.2

Children 1–8 years of age previously receiving bronchodilators alone: 0.5 mg daily, given in 1 or 2 divided doses.2 28

Children 1–8 years of age previously receiving inhaled corticosteroids: Initially, 0.5 mg daily, given in 1 or 2 divided doses.2 If response is inadequate, dosage may be increased to a maximum of 1 mg daily and/or administered in divided doses.2

Children 1–8 years of age previously receiving oral corticosteroids: 1 mg daily, given in 1 or 2 divided doses.2

Budesonide/Formoterol Fixed-combination Therapy
Oral Inhalation Aerosol

Adolescents ≥12 years of age not currently receiving an orally inhaled corticosteroid: Initially, 160 or 320 mcg of budesonide and 9 mcg of formoterol fumarate dihydrate twice daily, depending on asthma severity.g

Adolescents ≥12 years of age inadequately controlled with low-to-medium dosages of an inhaled corticosteroid: Initially, 160 mcg of budesonide and 9 mcg of formoterol fumarate dihydrate twice daily.g

Adolescents ≥12 years of age inadequately controlled with medium-to-high dosages of an inhaled corticosteroid: Initially, 320 mcg of budesonide and 9 mcg of formoterol fumarate dihydrate twice daily.g

If control of asthma is inadequate after 1–2 weeks of therapy at the lower dosage, a higher strength (higher strengths contain higher dosages of budesonide only) may provide additional asthma control.g

Adults

Crohn’s Disease
Management of Mild to Moderately Active Crohn’s Disease
Oral

Initially, 9 mg daily in the morning for 8 weeks.1 6

In patients who have not experienced remission during the initial 8-week course,28 29 a second 8-week course (16 weeks of continuous therapy) may be used.1 6 28 29

Maintenance of Remission
Oral

6 mg once daily for up to 3 months.1 40 If symptom control is maintained at 3 months, attempt to taper dosage to complete cessation.1 The manufacturer states that continued therapy beyond 3 months has not been shown to provide substantial clinical benefit.1

Asthma
Maintenance Monotherapy
Oral Inhalation Powder (Pulmicort Turbuhaler)

Previously receiving bronchodilators alone: Initially, 160–320 mcg (labeled 200–400 mcg) twice daily.3 a If required, dosage may be increased to a maximum of 320 mcg (labeled 400 mcg) twice daily.3 a

Previously receiving inhaled corticosteroids: Initially, 160–320 mcg (labeled 200–400 mcg) twice daily.3 a If required, may increase dosage to a maximum 640 mcg (labeled 800 mcg) twice daily.3 a

In patients with mild-to-moderate asthma whose asthma is adequately controlled with inhaled corticosteroids, consider 160 or 320 mcg (labeled 200 or 400 mcg, respectively) once daily.3 a

Pulmicort Turbuhaler in adults previously receiving oral corticosteroids: Initially, 320–640 mcg (labeled 400–800 mcg) twice daily.3 a If required, may increase dosage to a maximum of 640 mcg (labeled 800 mcg) twice daily.3 a

Oral Inhalation Powder (Pulmicort Flexhaler)

Usual initial dosage is 320 mcg (labeled 360 mcg) twice daily.j In some patients and in well-controlled patients, an initial dosage of 160 mcg (labeled 180 mcg) twice daily may be adequate.j If required, may increase dosage to a maximum of 640 mcg (labeled 720 mcg) twice daily.j

Budesonide/Formoterol Fixed-combination Therapy
Oral Inhalation Aerosol

Patients not currently receiving an orally inhaled corticosteroid: Initially, 160 or 320 mcg of budesonide and 9 mcg of formoterol fumarate dihydrate twice daily, depending on asthma severity.g

Patients inadequately controlled with low-to-medium dosages of an inhaled corticosteroid: Initially, 160 mcg of budesonide and 9 mcg of formoterol fumarate dihydrate twice daily.g

Patients inadequately controlled with medium-to-high dosages of an inhaled corticosteroid: Initially, 320 mcg of budesonide and 9 mcg of formoterol fumarate dihydrate twice daily.g

If control of asthma is inadequate after 1–2 weeks of therapy at the lower dosage, a higher strength (higher strengths contain higher dosages of budesonide only) may provide additional asthma control.g

Prescribing Limits

Pediatric Patients

Asthma
Maintenance Monotherapy
Oral Inhalation Powder

Pulmicort Turbuhaler in children ≥6 years of age: Maximum 320 mcg (labeled 400 mcg) twice daily.3 a

Pulmicort Flexhaler in children and adolescents 6–17 years of age: Maximum 320 mcg (labeled 360 mcg) twice daily.j

Oral Inhalation Suspension

Children 1–8 years of age, previously receiving bronchodilators alone: Maximum 0.5 mg daily.2 28

Children 1–8 years of age, previously receiving inhaled corticosteroids: Maximum 1 mg daily.2

Children 1–8 years of age, previously receiving oral corticosteroids: Maximum 1 mg daily.2

Budesonide/Formoterol Fixed-combination Therapy
Oral Inhalation Aerosol

Adolescents ≥12 years of age: Maximum 320 mcg of budesonide and 9 mcg of formoterol fumarate dihydrate twice daily.g

Adults

Asthma
Maintenance Monotherapy
Oral Inhalation Powder

Pulmicort Turbuhaler in patients previously receiving bronchodilators alone: Maximum 320 mcg (labeled 400 mcg) twice daily.3 a

Pulmicort Turbuhaler in patients previously receiving inhaled corticosteroids: Maximum 640 mcg (labeled 800 mcg) twice daily.3 a

Pulmicort Turbuhaler in patients previously receiving oral corticosteroids: Maximum 640 mcg (labeled 800 mcg) twice daily.3 a

Pulmicort Flexhaler in patients ≥18 years of age: Maximum 640 mcg (labeled 720 mcg) twice daily.j

Budesonide/Formoterol Fixed-combination Therapy
Oral Inhalation Aerosol

Maximum 320 mcg of budesonide and 9 mcg of formoterol fumarate dihydrate twice daily.g

Special Populations

Hepatic Impairment

Crohn’s Disease

Consider dosage reduction in moderate to severe hepatic impairment.1 6 (See Special Populations under Absorption in Pharmacokinetics.)

Asthma

No specific dosage recommendations at this time.g

Renal Impairment

Asthma

No specific dosage recommendations at this time.g

Geriatric Patients

Oral monotherapy: Careful dosage selection recommended due to possible age-related decrease in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Oral inhalation powder (Pulmicort Flexhaler): Careful dosage selection recommended due to possible age-related decrease in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.j

Fixed combination of budesonide and formoterol fumarate dihydrate: No dosage adjustment required.g (See Geriatric Use under Cautions.)

Cautions for Budesonide

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

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Withdrawal of Systemic Corticosteroid Therapy

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

Immunosuppressed Patients

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

Paradoxical Bronchospasm

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

Ocular Effects

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

Systemic Corticosteroid Effects

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

Musculoskeletal Effects

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.)

Concomitant Disease States

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

Infection

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

Other Effects

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

Use of Fixed Combinations

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

Specific Populations

Pregnancy

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

Lactation

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

Pediatric Use

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

Geriatric Use

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

Hepatic Impairment

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

Interactions for Budesonide

Metabolized by the CYP3A4 isoenzyme.1 2 3 6 31 g j

Drugs or Foods Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased plasma budesonide concentrations).1 2 3 6 31 g j

Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased plasma budesonide concentrations).1

Drugs Affecting GI pH

Potential pharmacokinetic interaction (may affect release properties and systemic absorption of enteric coated budesonide capsules).1 6

Specific Drugs or Food

Drug

Interaction

Comments

Antibiotics, macrolide (e.g., clarithromycin, erythromycin)

Increased systemic exposure of budesonide1 2 3 6 31 j

Monitor carefully if used concomitantly with oral budesonide capsules;2 3 31 consider reduction of budesonide dosage1 6 8

Antifungals, azole (e.g., itraconazole, ketoconazole)

Increased systemic exposure of budesonide1 2 3 6 31 g j

Monitor carefully if used concomitantly with oral budesonide capsules;3 31 consider reduction of budesonide dosage1 6 8

Use concomitantly with orally inhaled budesonide with cautiona g j

Antiretrovirals (indinavir, ritonavir)

Increased systemic exposure of budesonide1 2 3 6 31

Monitor carefully if used concomitantly with oral budesonide capsules;3 31 consider reduction of budesonide dosage1 6 8

Cimetidine

Increased peak plasma concentrations and rate of absorption of a non-enteric coated formulation of budesonide (not commercially available in US), resulting in substantial suppression of HPA axis1 6 28

Estrogens (i.e., oral contraceptives)

Pharmacokinetic interaction unlikely1 6 31

Formoterol

Pharmacokinetic interaction unlikelyg

Grapefruit juice

Increased systemic exposure of budesonide1 6

Avoid concomitant use1 6

Omeprazole

Pharmacokinetic interaction unlikely1 6 28 30

Budesonide Pharmacokinetics

Absorption

Bioavailability

Completely absorbed following oral administration,1 28 with peak plasma concentrations usually attained within 0.5–10 hours.1

Rapidly absorbed following administration as budesonide inhalation powder (Pulmicort Turbuhaler); peak plasma concentrations attained within 30 minutes.a

The absolute bioavailability of the inhalation suspension in asthmatic children (4–6 years of age) is 6%.2 Absolute systemic bioavailability of the inhalation powder in healthy individuals is 39%.a g j

The therapeutic effects of orally inhaled budesonide primarily result from local actions of the deposited inhaled dose on the respiratory tract rather than from the systemic actions of the swallowed portion of the dose.2 3 28 g j

Onset

Following continuous use of the oral inhalation of budesonide powder or the micronized suspension, improvement may occur within 1 or 2–8 days of therapy, respectively.2 3 24 28 j Optimum benefit occurs after 1–2 or 4–6 weeks of therapy with oral inhalation powder or suspension, respectively.2 3 24 25 28 j k

Food

Concomitant use of oral budesonide with grapefruit juice, a CYP3A4 isoenzyme inhibitor, increases twofold the systemic exposure of the drug.1 6 (See Specific Drugs or Food under Interactions.)

High-fat meal delays the time to peak drug concentration by 2.5 hours after oral administration;1 however, extent of absorption not affected.1

Special Populations

In patients with liver cirrhosis, increased systemic availability of oral budesonide.1 g j Patients with mild hepatic impairment affected minimally.1 Pharmacokinetics not studied in patients with severe hepatic impairment.1

Systemic availability of a single oral dose is higher in patients with Crohn’s disease, 6 8 12 28 31 32 33 34 but approaches that in healthy individuals following multiple dosing.1 4

Distribution

Extent

Glucocorticoids cross the placentae and are distributed into breast milk.1 g j

Plasma Protein Binding

85–90%; little or no binding to corticosteroid binding globulin.1 g j

Elimination

Metabolism

Metabolized by CYP3A4 isoenzyme to metabolites with negligible glucocorticoid activity.1 2 3 6 7 28 31 g j

Elimination Route

Excreted in urine (60%) and feces as metabolites following oral administration.1 g

Half-life

Terminal half life is 2–3 hours following oral inhalation.a f g

Special Populations

In patients with renal impairment, pharmacokinetics of oral budesonide not studied.1 However, since only metabolites with negligible glucocorticoid activity are excreted by the kidneys, increased adverse effects are not expected in such patients.1

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).1

Oral Inhalation

Powder for Inhalation

Tight, moisture-resistant containers at 20–25°C.a j k

Inhalation Suspension

20–25°C; protect from light and keep container in upright position.2 d

Inhalation Aerosol

20–25°C; store inhaler with mouthpiece down.g

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Stability and safety of budesonide suspension mixed with other drugs in a nebulizer not established; oral inhalation suspension for nebulization should not be mixed with other drugs.2 28

Actions

  • Appears to have immunosuppressant and substantial topical anti-inflammatory activity and lower systemic availability than conventional corticosteroids.4 6 7 9 11 12 28 31

  • Decreases inflammation by stabilizing leukocyte lysosomal membranes, preventing release of destructive acid hydrolases from leukocytes, or reducing leukocyte adhesion to capillary endothelium.e

  • Inhibits macrophage accumulation in inflamed areas.e

  • Reduces capillary wall permeability and edema formation.e

  • Antagonizes histamine activity and release of kinin from substrates.e

  • Reduces fibroblast proliferation, collagen deposition, and subsequent scar tissue formation.e

  • Stimulates erythroid cells of bone marrow, prolongs survival time of erythrocytes and platelets, and produces neutrophilia and eosinopenia.e

  • Promotes gluconeogenesis, redistribution of fat from peripheral to central areas of the body, and protein catabolism, which results in negative nitrogen balance.e

  • Reduces intestinal absorption and increases renal excretion of calcium.e

  • Suppresses the immune response by reducing activity and volume of the lymphatic system, producing lymphocytopenia.e

  • Decreases immunoglobulin and complement concentrations and passage of immune complexes through basement membranes.e

  • Depresses reactivity of tissue to antigen-antibody interactions.e

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Importance of providing the patient a copy of the manufacturer’s patient information and medication guide.2 3 g h

  • Importance of understanding of proper storage, preparation, and inhalation techniques, including use of the inhalation delivery systems.2 3 g

  • Necessity of swallowing capsules whole, without chewing or breaking.1

  • Importance of avoiding concomitant use of capsules with grapefruit juice.1 28

  • Importance of rinsing the mouth after oral inhalation.d g h j

  • Advise that oral inhalation must be used at regular intervals to be therapeutically effective.2 3 24 25 Importance of adherence to prescribed dosage, including not altering the dose or frequency of use unless otherwise instructed by a clinician.2 3 h i j k

  • Importance of advising patient that if a dose is missed, the next dose should be taken at the regularly scheduled time; the dose should not be doubled.d g h i k

  • Importance of patients not discontinuing or changing any medications used to control breathing problems without medical supervision, since worsening of asthma may occur.g h k

  • Importance of contacting a clinician if decreased effectiveness of a short-acting β2-adrenergic agonist (requiring more inhalations than usual) for acute symptoms occurs.g h i k

  • Advise that symptomatic relief of asthma will occur within 1 or 2–8 days of therapy with oral inhalation powder, inhalation aerosol, or inhalation suspension, respectively.2 3 24 25 28 g j Optimum effects may require at least 1–2, 2, or 4–6 weeks of therapy with oral inhalation powder, inhalation aerosol, or inhalation suspension, respectively.2 3 24 25 28 g j k

  • Importance of contacting a clinician if asthma symptoms do not improve or worsen after 1–2 weeks of regular therapy with budesonide alone or 1week of regular therapy with budesonide in fixed combination with formoterol fumarate dihydrate.h i

  • Advise that orally inhaled budesonide alone or in fixed combination with formoterol should not be used as a bronchodilator or for emergency use (e.g., relief of acute bronchospasm).2 3 24 25 g h k

  • Importance of contacting a clinician or obtaining medical care immediately if breathing problems worsen quickly.2 3 24 25 h j

  • Importance of informing patients that long-term use of inhaled corticosteroids may increase the risk for development of some eye problems (cataracts or glaucoma).d g h i j k Importance of regular eye examinations.d h j k

  • Importance of informing patients of potential for growth suppression in children.d g h i j k

  • Advise patients receiving orally inhaled glucocorticoid therapy who are currently being withdrawn or who have been withdrawn from systemic therapy to immediately resume full therapeutic dosages of systemic glucocorticoids and to contact their clinician for further instructions during stressful periods (e.g., severe infection, severe asthmatic attack).2 3 6 28

  • Patients should carry identification cards listing the diseases for which they are being treated, the glucocorticoid they are receiving and its dosage, and the name and telephone number of their physician.2 3 28 Patients being transferred from systemic corticosteroid to oral inhalation therapy should carry special identification (e.g., card, bracelet) indicating the need for supplementary systemic corticosteroids during periods of stress.2 3 28 j

  • In immunosuppressed patients, importance of avoiding exposure to chickenpox or measles, and, if exposed, of immediately consulting their clinician.2 3 g j k Importance of informing clinician of prior exposure to chickenpox or measles.h i j

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2 g h i j k

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., history of use of oral corticosteroids) and OTC drugs, vitamins, and herbal supplements, as well as any concomitant illnesses (e.g., osteoporosis, tuberculosis, other infections) or any allergies to orally inhaled corticosteroids.1 2 a d h i j k

  • Importance of advising patients of other important precautionary information.1 2 a (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Budesonide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, delayed-release (containing enteric-coated granules)

3 mg

Entocort EC

AstraZeneca

Oral Inhalation

Powder, for oral inhalation only

90 mcg (delivers 80 mcg per inhalation)

Pulmicort Flexhaler

AstraZeneca

180 mcg (delivers 160 mcg per inhalation)

Pulmicort Flexhaler

AstraZeneca

200 mcg (delivers 160 mcg per inhalation)

Pulmicort Turbuhaler

AstraZeneca

Suspension, for nebulization

0.25 mg/2 mL

Pulmicort Respules (available in flexible ampuls)

AstraZeneca

0.5 mg/2 mL

Pulmicort Respules (available in flexible ampuls)

AstraZeneca

Budesonide Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral Inhalation Only

Aerosol

80 mcg with Formoterol Fumarate Dihydrate 4.5 mcg per metered spray

Symbicort (with hydrofluoroalkane propellant and povidone)

AstraZeneca

160 mcg with Formoterol Fumarate Dihydrate 4.5 mcg per metered spray

Symbicort (with hydrofluoroalkane propellant and povidone)

AstraZeneca

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Budesonide 3MG 24-hr Capsules (MYLAN): 30/$459.97 or 90/$1,326.01

Entocort EC 3MG 24-hr Capsules (ASTRAZENECA): 30/$549.97 or 90/$1,559.96

Pulmicort Flexhaler 180MCG/ACT Aerosol (ASTRAZENECA LP): 1/$159.98 or 3/$455.95

Pulmicort Flexhaler 90MCG/ACT Aerosol (ASTRAZENECA LP): 1/$121.99 or 3/$335.99

Symbicort 160-4.5MCG/ACT Aerosol (ASTRAZENECA LP): 10/$232.99 or 31/$666.99

Symbicort 80-4.5MCG/ACT Aerosol (ASTRAZENECA LP): 10/$204.98 or 31/$591.99

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. AstraZeneca. Entocort EC (budesonide capsules) prescribing information. Wilmington, DE; 2005 Apr.

2. AstraZeneca. Pulmicort Respules (budesonide inhalation suspension) prescribing information. Wilmington, DE; 2003 Mar.

3. AstraZeneca. Pulmicort Turbuhaler (budesonide inhalation powder) prescribing information. Wilmington, DE; 2001 Dec.

4. Thomsen O, Cortot A, Jewel D et al. Budesonide and mesalazine in active Crohn’s disease: a comparison of the effects on quality of life. Am J Gastroenterol. . 2002; 97:649-53. [IDIS 478130] [PubMed 11922560]

5. Feagan BG, Sandborn WJ. Initial therapy for mild to moderate Crohn’s disease: mesalamine or budesonide? Rev Gastroenterol Disord. 2002; 2 (Suppl 2):S9-S15.

6. McKeage K, Goa KL. Budesonide (Entecort EC capsules): a review of its therapeutic use in the management of active Crohn’s disease in adults. Drugs. 2002; 62:2263-82. [PubMed 12381231]

7. Tremaine WJ, Hanauer SB, Katz et al. Budesonide CIR capsules (once or twice daily divided-dose) in active Crohn’s disease: a randomized placebo-controlled study in the United States. Am J Gastroenterol. 2002; 97:1748-54. [IDIS 483492] [PubMed 12135030]

8. Valentine JF. Treatment of Crohn’s disease with budesonide: this rose still has thorns! Am J Gastroenterol. 2002; 97:785-6.

9. Thomsen OO, Cortot A, Jewell D et al. Budesonide and mesalazine in active Crohn’s disease: a comparison of the effects on quality of life. Am J Gastroenterol. 2002; 97:649-53. [IDIS 478130] [PubMed 11922560]

10. Levine A, Broide E, Stein M. Evaluation of oral budesonide for treatment of mild and moderate exacerbations of Crohn’s disease in children. J Pediatr. 2002;140:75-80.

11. Greenberg GR, Feagan BG, Martin F et al. Oral budesonide for active Crohn’s disease. N Engl J Med. 1994; 331:836-41. [IDIS 335906] [PubMed 8078529]

12. Rutgeerts P, Löfberg R, Malchow H et al. A comparison of budesonide with prednisolone for active Crohn’s disease. N Engl J Med. 1994; 331:842-5. [IDIS 335907] [PubMed 8078530]

13. Sachar DB. Budesonide for inflammatory bowel disease. N Engl J Med. 1994; 331:873-4. [IDIS 335908] [PubMed 8078535]

14. Gregg I. The importance of patient education in the use of inhaled steroids. In: Mygind N, Clark TJH, eds. Topical steroid treatment for asthma and rhinitis. London: Bailliere Tindall; 1980:137-42.

15. Campieri M, Ferguson A, Doe W et al, for the Global Budesonide Study Group. Oral budesonide is as effective as oral prednisolone in active Crohn’s disease. Gut 1997;41:209-14.

16. Thomsen OO, Cortot A, Jewell D et al, for International Budesonide-Mesalamine Study Group. A comparison of budesonide and mesalamine for active Crohn’s disease. N Engl J Med. 1998;339:370-4.

17. Greenberg GR, Feagan BG, Martin F et al et al. Oral budesonide as maintenance treatment for Crohn’s disease: a placebo-controlled, dose-ranging study. Gastroenterology. 1996; 110:45-51. [IDIS 360622] [PubMed 8536887]

18. Lofberg R, Rutgeerts P, Malchow H et al. Budesonide prolongs time to relapse in ileal and ileocaecal Crohn’s disease: a placebo controlled one year study. Gut. 1996; 39:82-6. [IDIS 370136] [PubMed 8881815]

19. National Institutes of Health, National Heart, Lung, and Blood Institute. Global Initiative for asthma: global strategy for asthma management and prevention NHLBI/WHO Workshop Report. Bethesda, MD: National Institutes of Health. 2002 Feb. NIH/NHLBI Publication No. 02-3659. Available at: . Accessed Sep. 26, 2002.

20. O’Connell EJ. Efficacy of budesonide in moderate to severe asthma. Clin Ther. 2002; 24:887-905. [IDIS 483638] [PubMed 12117080]

21. Szefler SJ, Eigen H. Budesonide inhalation suspension: a nebulized corticosteroid for persistent asthma. J Allergy Clin Immunol. 2002;109:730-42.

22. Banov CH, Howland WC 3rd, Lumry WR. Once-daily budesonide via Turbuhaler improves symptoms in adults with persistent asthma. Ann Allergy Asthma Immunol. 2001; 86:627-32. [IDIS 465560] [PubMed 11428734]

23. Szefler SJ. A review of budesonide inhalation suspension in the treatment of pediatric asthma. Pharmacotherapy 2001 Feb;21 (2):195-206.

24. AstraZeneca. Pulmicort Respules (budesonide) inhalation suspension patient information. Wilmington, DE, 2002 Oct.

25. AstraZeneca. Pulmicort Turbuhaler (budesonide) inhalation powder patient information. Wilmington, DE, 2002 Nov. From the AstraZeneca web site . Accessed March 6, 2003.

26. Kane SV, Schoenfeld P, Sandborn WJ et al. The effectiveness of budesonide therapy for Crohn’s disease. Aliment Pharmacol Ther. 2002; 16:1509-17. [PubMed 12182751]

27. National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma update on selected topics—2002. J Allergy Clin Immunol. 2002; 110(Suppl 5):S141-219.

28. AstraZeneca, Wilmington, DE: Personal communication.

29. Thomsen O, Cortot A, Jewell D et al. Modified-release budesonide versus mesalazine in active Crohn’s disease: are there benefits in continuing treatment after 8 weeks? Gut. 2001; 49 (Suppl III): Abstract No. 2022.

30. Lundin P, Edsbäcker S, Seidegàrd JE. Budesonide (Entocort) capsules show a limited drug-drug interaction potential. Gut. 2001; 49(Suppl III): Abstract No.

31. Edsbäcker S. Budesonide capsules: scientific basis. Drugs Today. 2000; 36(Suppl G):9-23.

32. Lundin P, Edsbäcker S, Larsson P. Targeted delivery of oral budesonide (Entecort capsules) in healthy volunteers and Crohn’s disease patients. Gastroenterology. 2001; 120(Suppl 1): A-749: Abstract No.

33. Lindquist B. Budesonide CIR capsules in children and adults with Crohn’s disease: a pharmacokinetic and tolerability study. Gastroenterology. 1999; 116(Suppl 4): A-785: Abstract No.

34. Lundin PDP, Edsbäcker S, Bergstrand M et al. Pharmacokinetics of budesonide controlled ileal release capsules in children and adults with active Crohn’s disease. Aliment Pharmacol. 2003; 17:85-92.

35. Bar-Meir S, Chowers Y, Lavy A et al, for the Israeli Budesonide Study Group. Budesonide versus prednisone in the treatment of active Crohn’s disease. Gastroenterology. 1998; 115:835-40.

36. Steinhart AH, Ewe K, Griffiths AM et al. Corticosteroids for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev. 2003;(4):CD000301.

37. Ferguson A, Campieri M, Doe W et al et al. Oral budesonide as maintenance therapy in Crohn’s disease--results of a 12-month study. Aliment Pharmacol Ther. 1998; 12:175-83. [PubMed 9692692]

38. Sandborn WJ. Evidence-based treatment algorithm for mild to moderate Crohn’s disease. Am J Gastroenterol. 2003; 98(12 Suppl):S1-5.

39. Levine A, Weizman Z, Broide E et al for the Israeli Pediatric Gastroenterology Association Budesonide Study Group. A comparison of budesonide and prednisone for the treatment of active pediatric Crohn disease. J Pediatr Gastroenterol Nutr. 2003; 36:248-52. [PubMed 12548062]

40. Sandborn WJ, LöfbergR, Feagan BG et al. Budesonide for maintenance of remission in patients with Crohn’s disease in medically induced remission: a predetermined pooled analysis of four randomized, double-blind, placebo-controlled rials. Am J Gastroenterol. 2005; 100: 1780-7. [PubMed 16086715]

a. AstraZeneca. Pulmicort Turbuhaler (budesonide inhalation powder) prescribing information. Wilmington, DE; 2006 Oct.

d. AstraZeneca. Pulmicort Respules (budesonide) inhalation suspension patient information. Wilmington, DE; 2007 Feb.

e. AHFS Drug Information 2007. McEvoy GK, ed. Corticosteroids General Statement. Bethesda, MD: American Society of Health-System Pharmacists; 2007:3024-37.

f. AstraZeneca. Pulmicort Respules (budesonide inhalation suspension) prescribing information. Wilmington, DE; 2007 Jun.

g. AstraZeneca L.P. Symbicort (budesonide and formoterol fumarate dihydrate) inhalation aerosol prescribing information. Wilmington, DE; 2007 Oct.

h. Food and Drug Administration. Symbicort (budesonide and formoterol fumarate dihydrate) inhalation aerosol medication guide [May 2007: AstraZeneca]. Rockville, MD; FDA action date 2007 Oct 31. From Drugs@FDA website .

i. AstraZeneca L.P. Pulmicort Turbuhaler (budesonide) inhalation powder patient information. Wilmington, DE, 2006 Oct. From the AstraZeneca web site . Accessed Feb. 7, 2008.

j. AstraZeneca L.P. Pulmicort Flexhaler (budesonide) inhalation powder prescribing information. Wilmington, DE; 2007 Aug.

k. AstraZeneca L.P. Pulmicort Flexhaler (budesonide) inhalation powder patient information and instructions for use. Wilmington, DE; 2007 Aug.

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