Budesonide

Pronunciation

(byoo DES oh nide)

U.S. Brand Names

Entocort™ EC; Pulmicort Respules®; Pulmicort Turbuhaler®; Rhinocort® Aqua®

Generic Available

Canadian Brand Names

Entocort®; Gen-Budesonide AQ; Pulmicort®; Rhinocort® Turbuhaler®

Use

Intranasal: Children 6 years of age and Adults: Management of symptoms of seasonal or perennial rhinitis

Nebulization: Children 12 months to 8 years: Maintenance and prophylactic treatment of asthma

Oral capsule: Treatment of active Crohn's disease (mild to moderate) involving the ileum and/or ascending colon

Oral inhalation: Maintenance and prophylactic treatment of asthma; includes patients who require corticosteroids and those who may benefit from systemic dose reduction/elimination

Pregnancy Risk Factor

C/B (Pulmicort Respules® and Turbuhaler®, Rhinocort® Aqua®)

Pregnancy Implications

Use only if potential benefit to the mother outweighs the possible risk to the fetus. Studies of pregnant women using inhaled budesonide have not demonstrated an increased risk of abnormalities. Hypoadrenalism has been reported in infants.

Lactation

Enters breast milk/use caution

Contraindications

Hypersensitivity to budesonide or any component of the formulation

Inhalation: Contraindicated in primary treatment of status asthmaticus, acute episodes of asthma; not for relief of acute bronchospasm

Warnings/Precautions

May cause hypercorticism and/or suppression of hypothalamic-pituitary-adrenal (HPA) axis, particularly in younger children or in patients receiving high doses for prolonged periods. Particular care is required when patients are transferred from systemic corticosteroids to products with lower systemic bioavailability (ie, inhalation). May lead to possible adrenal insufficiency or withdrawal from steroids, including an increase in allergic symptoms. Patients receiving prolonged therapy of

20 mg per day of prednisone (or equivalent) may be most susceptible. Aerosol steroids do not provide the systemic steroid needed to treat patients having trauma, surgery, or infections.

Controlled clinical studies have shown that orally-inhaled and intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients. (In studies of orally-inhaled corticosteroids, the mean reduction in growth velocity was approximately 1 centimeter per year [range 0.3-1.8 cm per year] and appears to be related to dose and duration of exposure.) To minimize the systemic effects of orally-inhaled and intranasal corticosteroids, each patient should be titrated to the lowest effective dose. Growth should be routinely monitored in pediatric patients.

May suppress the immune system, patients may be more susceptible to infection. Use with caution in patients with systemic infections or ocular herpes simplex. Avoid exposure to chickenpox and measles. Corticosteroids should be used with caution in patients with diabetes, hypertension, osteoporosis, peptic ulcer, glaucoma, cataracts, or tuberculosis. Use caution in hepatic impairment. Enteric-coated capsules should not be crushed or chewed.

Adverse Reactions

Reaction severity varies by dose and duration; not all adverse reactions have been reported with each dosage form.

>10%:

Central nervous system: Oral capsule: Headache (up to 21%)

Gastrointestinal: Oral capsule: Nausea (up to 11%)

Respiratory: Respiratory infection, rhinitis

Miscellaneous: Symptoms of HPA axis suppression and/or hypercorticism (acne, easy bruising, fat redistribution, striae, edema) may occur in >10% of patients following administration of dosage forms which result in higher systemic exposure (ie, oral capsule), but may be less frequent than rates observed with comparator drugs (prednisolone). These symptoms may be rare (<1%) following administration via methods which result in lower exposures (topical).

1% to 10%:

Cardiovascular: Syncope, edema, hypertension

Central nervous system: Chest pain, dysphonia, emotional lability, fatigue, fever, insomnia, migraine, nervousness, pain, dizziness, vertigo

Dermatologic: Bruising, contact dermatitis, eczema, pruritus, pustular rash, rash

Endocrine & metabolic: Hypokalemia, adrenal insufficiency

Gastrointestinal: Abdominal pain, anorexia, diarrhea, dry mouth, dyspepsia, gastroenteritis, oral candidiasis, taste perversion, vomiting, weight gain, flatulence

Hematologic: Cervical lymphadenopathy, purpura, leukocytosis

Neuromuscular & skeletal: Arthralgia, fracture, hyperkinesis, hypertonia, myalgia, neck pain, weakness, paresthesia, back pain

Ocular: Conjunctivitis, eye infection

Otic: Earache, ear infection, external ear infection

Respiratory: Bronchitis, bronchospasm, cough, epistaxis, nasal irritation, pharyngitis, sinusitis, stridor

Miscellaneous: Allergic reaction, flu-like syndrome, herpes simplex, infection, moniliasis, viral infection, voice alteration

<1%: Aggressive reactions, alopecia, angioedema, avascular necrosis of the femoral head, depression, dyspnea, hoarseness, hypersensitivity reactions (immediate and delayed; include rash, contact dermatitis, angioedema, bronchospasm), intermenstrual bleeding, irritability, nasal septum perforation, osteoporosis, psychosis, somnolence

Postmarketing and/or case reports: Growth suppression, benign intracranial hypertension

Overdosage/Toxicology

Inhaled formulations: Symptoms of overdose include irritation and burning of the nasal mucosa, sneezing, intranasal and pharyngeal Candida infections, nasal ulceration, epistaxis, rhinorrhea, nasal stuffiness, headache.

When consumed in excessive quantities, systemic hypercorticism and adrenal suppression may occur, in those cases discontinuation and withdrawal of the corticosteroid should be done judiciously. Treatment should be symptomatic and supportive.

Drug Interactions

Substrate of CYP3A4 (major)

Cimetidine: Decreased clearance and increased bioavailability of budesonide

CYP3A4 inhibitors: Serum level and/or toxicity of budesonide may be increased; this effect was shown with ketoconazole, but not erythromycin. Other potential inhibitors include amiodarone, cimetidine, clarithromycin, delavirdine, diltiazem, dirithromycin, disulfiram, fluoxetine, fluvoxamine, grapefruit juice, indinavir, itraconazole, ketoconazole, nefazodone, nevirapine, propoxyphene, quinupristin-dalfopristin, ritonavir, saquinavir, verapamil, zafirlukast, zileuton.

Proton pump inhibitors (omeprazole, pantoprazole, rabeprazole): Theoretically, alteration of gastric pH may affect the rate of dissolution of enteric-coated capsules. Administration with omeprazole did not alter kinetics of budesonide capsules.

Salmeterol: The addition of salmeterol has been demonstrated to improve response to inhaled corticosteroids (as compared to increasing steroid dosage).

Ethanol/Nutrition/Herb Interactions

Food: Grapefruit juice may double systemic exposure of orally-administered budesonide. Administration of capsules with a high-fat meal delays peak concentration, but does not alter the extent of absorption.

Herb/Nutraceutical: St John's wort may decrease budesonide levels.

Stability

Nebulizer: Store upright at 20°C to 25°C (68°F to 77°F) and protect from light. Do not refrigerate or freeze. Once aluminum package is opened, solution should be used within 2 weeks. Continue to protect from light.

Nasal inhaler: Store with valve up at 15°C to 30°C (59°F to 86°F). Use within 6 months after opening aluminum pouch. Protect from high humidity.

Nasal spray: Store with valve up at 20°C to 25°C (68°F to 77°F) and protect from light. Do not freeze.

Mechanism of Action

Controls the rate of protein synthesis, depresses the migration of polymorphonuclear leukocytes, fibroblasts, reverses capillary permeability, and lysosomal stabilization at the cellular level to prevent or control inflammation

Pharmacodynamics/Kinetics

Onset of action: Respules®: 2-8 days; Rhinocort® Aqua®: ~10 hours; Turbuhaler®: 24 hours

Peak effect: Respules®: 4-6 weeks; Rhinocort® Aqua®: ~2 weeks; Turbuhaler®: 1-2 weeks

Absorption: Capsule: Rapid and complete

Distribution: 2.2-3.9 L/kg

Protein binding: 85% to 90%

Metabolism: Hepatic via CYP3A4 to two metabolites: 16 alpha-hydroxyprednisolone and 6 beta-hydroxybudesonide; minor activity

Bioavailability: Limited by high first-pass effect; Capsule: 9% to 21%; Respules®: 6%; Turbuhaler®: 6% to 13%; Nasal: 34%

Half-life elimination: 2-3.6 hours

Time to peak: Capsule: 30-600 minutes (variable in Crohn's disease); Respules®: 10-30 minutes; Turbuhaler®: 1-2 hours; Nasal: 1 hour

Excretion: Urine (60%) and feces as metabolites

Dosage

Nasal inhalation: (Rhinocort® Aqua®): Children 6 years and Adults: 64 mcg/day as a single 32 mcg spray in each nostril. Some patients who do not achieve adequate control may benefit from increased dosage. A reduced dosage may be effective after initial control is achieved.

Maximum dose: Children <12 years: 128 mcg/day; Adults: 256 mcg/day

Nebulization: Children 12 months to 8 years: Pulmicort Respules®: Titrate to lowest effective dose once patient is stable; start at 0.25 mg/day or use as follows:

Previous therapy of bronchodilators alone: 0.5 mg/day administered as a single dose or divided twice daily (maximum daily dose: 0.5 mg)

Previous therapy of inhaled corticosteroids: 0.5 mg/day administered as a single dose or divided twice daily (maximum daily dose: 1 mg)

Previous therapy of oral corticosteroids: 1 mg/day administered as a single dose or divided twice daily (maximum daily dose: 1 mg)

Oral inhalation:

Children 6 years:

Previous therapy of bronchodilators alone: 200 mcg twice initially which may be increased up to 400 mcg twice daily

Previous therapy of inhaled corticosteroids: 200 mcg twice initially which may be increased up to 400 mcg twice daily

Previous therapy of oral corticosteroids: The highest recommended dose in children is 400 mcg twice daily

Adults:

Previous therapy of bronchodilators alone: 200-400 mcg twice initially which may be increased up to 400 mcg twice daily

Previous therapy of inhaled corticosteroids: 200-400 mcg twice initially which may be increased up to 800 mcg twice daily

Previous therapy of oral corticosteroids: 400-800 mcg twice daily which may be increased up to 800 mcg twice daily

NIH Guidelines (NIH, 1997) (give in divided doses twice daily):

Children:

"Low" dose: 100-200 mcg/day

"Medium" dose: 200-400 mcg/day (1-2 inhalations/day)

"High" dose: >400 mcg/day (>2 inhalation/day)

Adults:

"Low" dose: 200-400 mcg/day (1-2 inhalations/day)

"Medium" dose: 400-600 mcg/day (2-3 inhalations/day)

"High" dose: >600 mcg/day (>3 inhalation/day)

Oral: Adults: Crohn's disease: 9 mg once daily in the morning; safety and efficacy have not been established for therapy duration >8 weeks; recurring episodes may be treated with a repeat 8-week course of treatment

Note: Treatment may be tapered to 6 mg once daily for 2 weeks prior to complete cessation. Patients receiving CYP3A4 inhibitors should be monitored closely for signs and symptoms of hypercorticism; dosage reduction may be required.

Dosage adjustment in hepatic impairment: Monitor closely for signs and symptoms of hypercorticism; dosage reduction may be required.

Administration

Inhalation: Inhaler should be shaken well immediately prior to use; while activating inhaler, deep breathe for 3-5 seconds, hold breath for ~10 seconds and allow 1 minute between inhalations. Rinse mouth with water after use to reduce aftertaste and incidence of candidiasis.

Nebulization: Shake well before using. Use Pulmicort Respules® with jet nebulizer connected to an air compressor; administer with mouthpiece or facemask. Do not use ultrasonic nebulizer. Do not mix with other medications in nebulizer. Rinse mouth following treatments to decrease risk of oral candidiasis (wash face if using face mask).

Oral capsule: Capsule should be swallowed whole; do not crush or chew.

Monitoring Parameters

Monitor growth in pediatric patients.

Dietary Considerations

Avoid grapefruit juice when using oral capsules.

Patient Education

Use as directed; do not increase dosage or discontinue abruptly without consulting prescriber. May be more susceptible to infection; avoid exposure to chickenpox and measles unless immunity has been established. If exposure to measles or chickenpox occurs, notify your prescriber immediately. Report acute nervousness or inability to sleep; severe sneezing or nosebleed; respiratory difficulty, sore throat, hoarseness, or bronchitis; respiratory difficulty or bronchospasms; disturbed menstrual pattern; vision changes; loss of taste or smell perception; or worsening of condition or lack of improvement. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.

Oral capsule: Swallow whole; do not crush or chew capsule.

Inhalation/nebulization: This is not a bronchodilator and will not relieve acute asthma attacks. It may take several days for you to realize full effects of treatment. If you are also using an inhaled bronchodilator, wait 10 minutes before using this steroid aerosol. Take 5-10 deep breaths. Use inhaler on inspiration. Hold breath for 5-10 seconds after inhalation. Allow 1 full minute between inhalations. You may experience dizziness, anxiety, or blurred vision (rise slowly from sitting or lying position and use caution when driving or engaging in tasks requiring alertness until response to drug is known); or taste disturbance or aftertaste (frequent mouth care and mouth rinses may help). Rinse mouth with water following oral treatments to decrease risk of oral candidiasis (wash face if using a face mask).

Additional Information

Effects of inhaled/intranasal steroids on growth have been observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally-inhaled and intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for "catch up" growth following discontinuation of treatment with inhaled corticosteroids has not been adequately studied.

Cardiovascular Considerations

Inhaled steroid therapy, usually used for chronic obstructive lung disease, has the important advantage of having minimal systemic effects. The inhaled steroid, when administered appropriately, may be assumed to have pulmonary effects equivalent to about 10 mg of oral steroids but with minimal systemic consequences.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation), dry throat, abnormal taste, and herpes simplex. Localized infections with Candida albicans or Aspergillus niger have occurred frequently in the mouth and pharynx with repetitive use of oral inhaler of corticosteroids. These infections may require treatment with appropriate antifungal therapy or discontinuance of treatment with corticosteroid inhaler.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause nervousness and insomnia

Mental Health: Effects on Psychiatric Treatment

None reported

Dosage Forms

Capsule, enteric coated (Entocort™ EC): 3 mg

Powder for oral inhalation (Pulmicort Turbuhaler®): 200 mcg/inhalation (104 g) [delivers ~160 mcg/inhalation; 200 metered doses]

Additional dosage strengths available in Canada: 100 mcg/inhalation, 400 mcg/inhalation

Suspension, nasal spray (Rhinocort® Aqua®): 32 mcg/inhalation (8.6 g) [120 metered doses]

Suspension for oral inhalation (Pulmicort Respules®): 0.25 mg/2 mL (30s), 0.5 mg/2 mL (30s)

References

Expert Panel Report 2, "Guidelines for the Diagnosis and Management of Asthma," Clinical Practice Guidelines , National Institutes of Health, National Heart, Lung, and Blood Institute, NIH Publication No. 94-4051, April, 1997.

International Brand Names

Aerosial® (MX); Aerovial® (CL); Aerovial Nasal® (CL); Aircort® (IT); Apulein® (CZ, HU, RO, RU); Aquacort® (DE); B-Cort bronquial® (CO); B-Cort nasal acuso® (CO); Benacort® (RU); Benosid® (DE); Bidien® (IT); Budamax® (AU); Budapp® (DE); Budecort® (BR, DE, TH); Budefarma® (AR); Budefat® (DE); BudeLich® (DE); Budenofalk® (BE, CH, CZ, DE, GB, HU, ID, IE, PL, RO, SG, SI, TR); Budenosida Nasal Merck® (ES); Buderhin® (PL); Budes® (DE); Budeson Aqua® (AR); Budeson® (AR, IL); Budeson Forte® (AR); Budesonida Aldo Union® (ES); Budesonid acis® (DE); Budesonid AL® (DE); Budesonida Nasal Aldo Un® (ES); Budesonida nasal Memphis® (CO); Budesonide Cyclocaps® (GB); Budesonide® (GB); Budesonide Inhalatiepoeder® (NL); Budesonide Nasal Merck® (ES); Budesonide Nevel® (NL); Budesonid Generics® (FI); Budesonid-GW® (HU); Budesonid Heumann® (DE); Budesonido Merck® (PT); Budesonid pädia® (DE); Budesonid® (PL, RO, RU, YU); Budesonid-ratiopharm® (DE); Budesonid Scand Pharm® (SE); Budesonid Stada® (DE); budesonid von ct® (DE); Budeson Nasal® (AR); Budeson Nebu® (AR); Budiair® (DE); Budicort® (IL); Budison® (DE); Budo-san® (AT, HR); Busonid® (BR); Butacort® (NZ); Clebudan® (CL); Clebudan Forte® (CL); Cortasm® (BR); Cortinasal® (CH); Cortivent® (FI); Cyclocaps Budesonid® (DE); Demotest® (ES); Desonax® (IT); Despex® (AR); Easi-Cort® (CZ); Eltair® (IT, NZ, SG, TH); Entocir® (IT); Entocord® (ES, ZA); Entocort® (AR, AT, AU, BE, BR, CA, CH, CY, CZ, DE, DK, FI, FR, GB, HU, IL, KW, LB, MT, NL, NO, NZ, PL, RO, SE, SG, TR); Entocort CIR® (CH); Entocort CR® (IE); Entocort Enema® (BE, BR, CH, ES, GB, LU, PT, SG); Esonide® (SG); Gen-Budesonide AQ (CA); Giona Easyhaler® (CZ); Hayclear® (NZ); Horacort® (PL); Inflammide® (CL, CO, CZ, EC, ID, SG, TH); Miflonid® (CZ); Miflonide® (AT, BE, CH, CO, DE, DK, ES, IL, IT, PL, PT, TR); Nasocort® (IL); Nastizol Hidrospray® (AR); Neo Rinactive® (ES); Neumotex® (AR); Novopulmon® (BR, DE); Olfex® (ES); Preferid® (IT, LU); Proetzonide® (AR); Pulmaxan® (IT); Pulmicort® (AT, AU, BE, BR, CA, CH, CO, CZ, DE, DK, ES, FI, FR, GB, HK, HU, ID, IE, IN, LU, MX, NL, NO, NZ, PL, PT, RO, SE, SG, TH, TR, YU); Pulmicort Orifarm® (DK); Pulmicort Paranova® (DK); Pulmicort Respules® (CH, GB, IE); Pulmicort® Topinasal® (DE); Pulmicort Turbohaler® (BE, BG, CH, CY, CZ, EG, FI, GB, IE, JO, KW, LB, MT, NO, SY); Pulmicort® Turbuhaler (BR, CL, DE, ES, HU, NZ, PL, RO, RU, SE, SI, TH, TR); Pulmicort Turbuhaler Europharma DK® (DK); Pulmicort Turbuhaler PharmaCoDane® (DK); Pulmictan® (ES); Pulmolisoflam® (AR); Pulmotide® (IL); Pulmovent® (SI, YU); Respicort® (DE); Rhinocort Aqua® (AT, BE, CO, CY, CZ, DK, EG, ES, FI, GB, HU, ID, JO, KW, LB, MT, RO, SE, SY, TH, TR, YU); Rhinocort® (AT, AU, BG, CH, CZ, DK, ES, FI, FR, HK, HU, IN, IT, LU, MX, NL, NO, NZ, PL, SE, SG, TR); Rhinocort Turbuhaler® (BE); Rhinocort® Turbuhaler® (CA); Rhinocort Turbuhaler® (DK, IE, NO, SE); Rhinosol® (DK); Ribujet® (ES); Rino-B® (AR); Spirocort® (AR, DK, IT); Tafen® (CZ, HR, PL, RO, SI); Timalar® (CO)

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