The most common adverse events during treatment with nasal budesonide are epistaxis (8%), pharyngitis (4%), cough (2%), and nasal irritation (2%). Dysosmia (reduced sense of smell) and nasal septum perforation have been reported with postmarketing use of nasal budesonide. During budesonide nebulization, the most common adverse reactions include respiratory infection (2.2% to 38% depending on the clinical trial), cough (5% to 9%), rhinitis (7% to 12%), and otitis media (9% to 12%). Otitis media occurred in 1.3% of patients who received budesonide inhalation powder in clinical trials. Other adverse events to oral or inhaled budesonide therapy include epistaxis (2% to 4% inhaled), pharyngitis (3% or more inhaled), rhinitis (greater than 2% to less than 5% oral, 2.2% to 12% inhaled), sinusitis (8% oral, 3% or more inhaled), nasal congestion (2.7 % inhaled), viral infection (6% oral, 2.2% to 5% inhaled), ear infection (less than 5% oral, 2% to 5% inhaled), otalgia (1 to less than 3% inhaled), urinary tract infection (greater than 2% to 5% oral), dysphonia (hoarseness) (1% to 3% inhaled), fever (more than 2% to less than 5% oral, greater than 3% inhaled, reported during postmarketing experience with rectal foam), and herpes simplex activation. Throat irritation has also been reported during postmarketing use of inhaled budesonide. Oral candidiasis is a well known adverse effect of inhaled corticosteroids; 3% to 4% of patients who received inhaled budesonide experienced oral candidiasis in clinical trials. Using an add-on spacer device, reducing the frequency of use, and rinsing the mouth after use may minimize the incidence of oropharyngeal thrush. In clinical trials of oral budesonide capsules, less than 5% of patients developed oral candidiasis. Monitor patients on long-term budesonide therapy for signs of infection. Discontinuation of budesonide may be required.[31824] [33486] [34376] [34979] [52910] [58166] [64318] Dyspnea was reported in 6% of patients taking oral budesonide for primary Immunglobulin A (IgA) nephropathy.[67192]

In general, oral budesonide is well tolerated. Delayed duodenal absorption and extensive first-pass metabolism reduces the amount of drug available for systemic absorption. The most common central nervous system reactions occurring with oral budesonide, independent of formulation (5% or more of patients, more than placebo) include headache (21% to 37%), dizziness (7%), and fatigue (5% to 8%). Many adverse events were reported with oral budesonide capsules in less than 5% of patients (but greater than placebo) including agitation, confusion, hyperkinesis, insomnia, nervousness, paresthesias, somnolence or drowsiness, tremor, and vertigo. Insomnia (4% to 6%), sleep changes (3% to 10%), and emotional lability (4% to 10%) have been reported with oral budesonide tablets. However, reports have noted the advantage of oral budesonide in lowering CNS toxicity that may occur with other oral steroids.[26692] [64318] Fatigue was reported in 5% of patients taking oral budesonide for primary Immunglobulin A (IgA) nephropathy.[67192] Headache (3%), migraine (1% to 3%), insomnia (1% to 3%), and fatigue (1% to 3%) have also been reported with inhaled budesonide. Psychiatric adverse reactions reported in less than 1% of patients receiving inhaled budesonide include depression, aggressive reactions, irritability, anxiety, and psychosis.[33486] [34376] [34979] [52910] In patients using budesonide rectal foam, insomnia, sleep disorder, and depression were reported in less than 1% of patients. Mood swings and dizziness were also reported during postmarketing experience with budesonide rectal foam and oral capsules.[52910] [58166]

Immediate or delayed hypersensitivity reactions, including anaphylactoid reactions, urticaria, angioedema, rash (unspecified), and bronchospasm have rarely been reported with budesonide therapy. Bronchospasm has also been reported in 2% of patients receiving nasal budesonide in clinical trials. Rash has been reported in 4% or less of patients and pruritus and ecchymosis in 1% to 3% of patients receiving inhaled budesonide. Ecchymosis has been reported in 10% of patients receiving oral budesonide. Contact dermatitis was reported in less than 5% of patients receiving oral budesonide capsules and in 1% to 3% of patients receiving inhaled budesonide. Additional dermatologic adverse reactions occurring in less than 5% of patients receiving oral budesonide but occurring at a rate greater than those receiving placebo in clinical trials included alopecia, hyperhidrosis (increased sweating), purpura, and eczema (atopic dermatitis).[31824] [33486] [34376] [34979] [52910] [64318] Dermatitis was reported in 7% of patients taking oral budesonide for primary Immunglobulin A (IgA) nephropathy.[67192] In patients using budesonide rectal foam, anaphylactoid reactions, pruritis, maculopapular rash, and allergic dermatitis were reported during postmarketing experience.[58166]

Budesonide therapy, just like any corticosteroid, has been rarely associated with the development of cataracts, increased ocular pressure or ocular hypertension, and glaucoma in adults. The risk of cataracts increases with long-term and high-dose inhaled corticosteroid use. The mechanism of corticosteroid-induced cataract formation is uncertain but may involve disruption of sodium-potassium pumps in the lens epithelium leading to accumulation of water in lens fibers and agglutination of lens proteins.[24813] Visual impairment has been reported in less than 5% of patients receiving oral budesonide, but cataract development has not been noted. Prolonged use of glucocorticoids could result in glaucoma or ocular nerve damage including optic neuritis. Temporary or permanent visual impairment, including blindness, has been reported with glucocorticoid administration by several routes of administration including intranasal administration. Secondary fungal and viral infections of the eye can be exacerbated by corticosteroid therapy. Ocular infection was reported in 1 to less than 3% of patients receiving inhaled budesonide therapy.[31824] [33486] [34376] [34979] [52910] [64318]

Pharmacologic doses of corticosteroids administered for prolonged periods can result in hypothalamic-pituitary-adrenal (HPA) suppression; symptoms of hypocorticism have been reported rarely with inhaled budesonide use. Adrenal insufficiency and withdrawal symptoms may occur after treatment discontinuation or when transitioning from systemic corticosteroids to inhaled corticosteroids in some patients. Exogenously administered corticosteroids exert negative feedback on the pituitary, which inhibits the secretion of adrenocorticotropin (ACTH). This results in a decrease in ACTH-mediated synthesis of endogenous corticosteroids and androgens by the adrenal cortex. The mean decrease in the integrated 0 to 24 hour plasma cortisol concentration as determined by data from subjects in a crossover study was 45% after 5 days of budesonide capsules (9 mg/day) and 78% after 5 days of prednisolone 20 mg/day. In 17% of 268 patients using budesonide rectal foam 2 mg/25 mL, decreases in serum cortisol levels associated with budesonide were seen at weeks 1 and 2 (twice-daily treatment), but gradually returned to baseline levels during the 4 weeks of once-daily treatment. Adrenocortical insufficiency was reported in 4% of 268 patients using budesonide rectal foam 2 mg/25 mL. The severity of glucocorticoid-induced secondary adrenocortical insufficiency varies among individuals and is dependent on the dose, frequency, time of administration, and duration of therapy. Use of inhaled corticosteroids with systemic corticosteroids could increase the likelihood of HPA suppression as compared with a therapeutic dose of either one alone.[31824] [33486] [34376] [34979] [52910] [58166] [64318]

Controlled clinical trials have shown that intranasal or orally inhaled corticosteroids may cause growth inhibition in pediatric patients. Growth inhibition has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients. With orally inhaled corticosteroids, the mean reduction in growth velocity is approximately one centimeter per year (range 0.3 to 1.8 cm per year) and appears to be related to the dose and duration of exposure. In one study, children 5 to 12 years of age with asthma receiving inhaled budesonide experienced a 1.1 cm reduction in growth compared to the placebo group by the end of 1 year. By the end of 4 years, the growth velocities of both groups were similar.[33486] In general, the benefits of regular inhaled corticosteroid (ICS) use outweigh the potential risk of relatively small and non-cumulative growth suppression in children with asthma; however, growth should be monitored.[57670] Further study is needed to determine the long-term effects of growth velocity reduction in children, including the impact on final adult height. To minimize the effects of inhaled corticosteroids, each patient should be titrated to the lowest effective dose.[34376] [33486] [34979] [52910] [58166] [64318]

Oral and inhaled corticosteroids may impact bone and joint health. In two 8-week placebo-controlled trials of oral budesonide tablets, arthralgia (5%) was listed among the most common adverse events reported. Prolonged use (e.g., more than 1 year) of high doses of inhaled corticosteroids, such as budesonide, especially when used in combination with frequent courses of systemic corticosteroids, may be associated with skeletal changes and reduced bone mineral density (BMD), which may increase the risk of osteopenia and osteoporosis. The clinical significance of small changes in BMD with regard to long-term outcomes, such as fracture, is unknown. Bone disorders including avascular necrosis of the femoral head and osteoporosis have been reported in less than 1% of patients receiving inhaled budesonide. In long-term (12 months) open-label studies for oral budesonide tablets, 77% of patients had normal bone density scans compared to 74% with placebo.[33486] [34376] [34979] [52910] [58166] [64318]

In clinical evaluation of oral budesonide, decreased blood cortisol (6% to 11%) and acne (2% to 6%) were listed among the most common adverse events reported. Other glucocorticoid related effects reported with either short term induction therapy (8 to 16 weeks) or long-term treatment (12 months) included, moon face or Cushingoid features (3%), fluid retention (1% to 3%), hirsutism (1% to 3%), and flushing (1% tablets, less than 5% capsules).[52910] [64318] In clinical trials evaluating the incidence of symptoms of hypercorticism (Cushing's syndrome) with oral budesonide versus prednisolone, only acne vulgaris (15% vs. 23%, respectively) and moon face (11% vs. 37%, respectively) were statistically less than prednisolone. Easy bruising (15%) and hirsutism (5%) occurred at a rate slightly higher than with prednisolone. Buffalo hump, swollen ankles and skin striae occurred at incidences similar to prednisolone.[34979] Acne (11%), face edema (6%), and hirsutism (5%) were reported in patients taking oral budesonide for primary Immunglobulin A (IgA) nephropathy.[67192] From postmarketing surveillance with oral budesonide, increased intracranial pressure (benign) has rarely been reported, but a causal relationship has not been established.[34979] Acne and hyperglycemia have been reported in less than 1% of patients using budesonide rectal foam and benign increased intracranial pressure has been reported during postmarketing experience.[58166]

Gastrointestinal (GI) adverse reactions reported in patients receiving budesonide include nausea (11% to 13% oral, 1.8% inhaled, 2% rectal foam), constipation (1% to 5% oral), dyspepsia (5% to 6% oral), abdominal distention (4% to 6% oral), abdominal pain (6% to 10% oral, 1% to 3% inhaled), flatulence (6% to 8% oral), vomiting (6% oral, 1% to 4% inhaled), diarrhea (10% oral, 2% to 4% inhaled), gastroenteritis (1.8% to 5% inhaled), weight gain (less than 5% and up to 7% oral, 1% to 3% inhaled), xerostomia (1% to 3% inhaled), dysgeusia (1% to 3% inhaled), and anorexia (1 to less than 3% inhaled). Additional GI adverse reactions occurring in less than 5% of patients receiving oral budesonide, but at an incidence higher than with placebo in clinical trials, included anus disorder, appetite stimulation, Crohn's disease aggravated, enteritis, epigastric pain, gastrointestinal fistula, glossitis, hemorrhoids, GI obstruction, tongue edema, and tooth disorder.[33486] [34376] [34979] [52910] [64318] [67192] Pancreatitis has been reported during postmarketing experience with budesonide rectal foam.[58166] Rectal GI bleeding has been reported during postmarketing experience with oral budesonide tablets.[52910]

Cardiovascular adverse reactions that occurred in less than 5% of patients receiving oral budesonide but at a greater incidence than with placebo included edema, flushing, hypertension, palpitations, and sinus tachycardia.[34979] [52910] [64318] Hypertension (16%) and peripheral edema (14%) were reported in patients taking oral budesonide for primary Immunglobulin A (IgA) nephropathy.[67192] Other cardiovascular adverse reactions reported in patients receiving budesonide include chest pain (unspecified) (less than 5% oral, 1% to 3% inhaled) and syncope (1% to 3% inhaled).[33486] [34376] [34979] [52910] [64318] In patients using budesonide rectal foam, hypertension and peripheral edema were reported during postmarketing experience.[58166]

In rare cases, patients on inhaled budesonide may present with eosinophilia and clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition often treated with systemic corticosteroids. These events have happened most commonly in association with systemic corticosteroid withdrawal in conjunction with the introduction of inhaled corticosteroid therapy. Patients presenting with eosinophilia, vasculitis with granulomas, worsening pulmonary symptoms, and/or neuropathy may have this condition, which may be severe. Similar cases have been reported with the use of other inhaled corticosteroids. A causal relationship to budesonide has not yet been established.[34376]

Musculoskeletal adverse reactions reported with budesonide therapy include musculoskeletal pain (5% oral; 3% or more inhaled), back pain (3% or more inhaled), neck pain (1% to 3% inhaled), hypertonia (1% to 3% inhaled), myalgia (less than 5% oral; 1% to 3% inhaled), muscle cramps (less than 5% oral), and arthritis (less than 5% oral).[33486] [34376] [34979] [64318] Muscle spasms were reported in 13% of patients taking oral budesonide for primary Immunglobulin A (IgA) nephropathy.[67192]

Generalized adverse reactions reported with budesonide therapy include asthenia (less than 5% oral), flu-like disorder (1 to less than 3% inhaled, less than 5% oral), and malaise (less than 5% oral).[33486] [34979] [64318]

Laboratory abnormalities reported in 1% or more of patients receiving oral budesonide in clinical trials, regardless of relationship to budesonide, include hypokalemia (1% to less than 5%), leukocytosis (1% to less than 5%), elevated C-reactive protein (1% to less than 5%), anemia, hematuria, pyuria, elevated erythrocyte sedimentation rate, elevated alkaline phosphatase, and atypical neutrophils. Leukocytosis is a common physiologic effect of systemic corticosteroid therapy and may need to be differentiated from the leukocytosis that occurs with inflammatory or infectious processes.[30943] [34979] [52910] [65096] [65097] [64318]

Inhaled budesonide is contraindicated as primary therapy for patients with status asthmaticus or other types of acute bronchospasm for which intensive therapy is warranted. Patients should be advised that budesonide is not to be used as a bronchodilator and is not indicated for relief of acute bronchospasm.[33486] [34376] Although inhaled corticosteroids (ICSs) are not indicated for primary treatment of an acute exacerbation, they may be initiated at any time during an exacerbation for patients not using long-term control therapy. An ICS may also be continued during an exacerbation for patients previously using the drug for chronic control.[37445] Additionally, budesonide is contraindicated for use in any patient with a known hypersensitivity to budesonide or any ingredient in the formulation.[33486] [34376] Pulmicort Flexhaler contains micronized lactose, which may contain trace or residual levels of milk protein. Patients with a severe milk protein hypersensitivity may experience an allergic reaction to this product.[34376]

Although inhaled budesonide is absorbed systemically to a lesser extent than other corticosteroids, significant amounts can be absorbed when large doses are administered and immunosuppression may occur. In general, corticosteroid therapy can mask the symptoms of infection and should not be used in cases of bacterial or viral infection that are not adequately controlled by anti-infective agents, except in life-threatening circumstances. Secondary infections are common during corticosteroid therapy. Corticosteroids can reactivate tuberculosis and should not be used in patients with a history of active tuberculosis except when chemoprophylaxis is instituted concomitantly. Corticosteroids should be avoided in patients with active herpes infection, including herpes simplex ocular infection. Extended use of budesonide nasal spray or inhalations has been rarely associated with the development of localized fungal infection with Candida albicans in the nose, mouth, and pharynx. If this develops, discontinuation of inhaled budesonide is warranted, and appropriate local therapy should be instituted. Patients who are on long-term budesonide inhalation therapy should receive periodic evaluation for nasal Candida infections or other adverse effects on the nasal mucosa.

Administration of corticosteroids may result in more serious or even fatal varicella (chickenpox) or measles infection in susceptible pediatric patients or adults. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is unknown. The clinical course of varicella infection or measles in patients treated with inhaled corticosteroids has not been studied; however, the immune-response to varicella vaccination in pediatric patients receiving budesonide therapy has. An open-label, non-randomized, clinical study examined the immune responsiveness of varicella vaccine in 243 asthma patients aged 12 months to 8 years who were treated with either budesonide inhalation suspension 0.25 to 1 mg daily (n=151) or non-corticosteroid asthma therapy (n=92) including beta-2-agonists and leukotriene receptor antagonists. The percentage of patients developing a seroprotective antibody titer of >= 5 (gpELISA value) in response to the vaccination was similar between the 2 groups (85% of patients treated with budesonide versus 90% of patients not receiving budesonide). None of the patients treated with budesonide developed chicken pox as a result of vaccination. Appropriate prophylactic medications should be considered in patients receiving budesonide who are exposed to varicella (VZIG or IVIG) or measles (IG). If varicella develops, treatment with antiviral agents may be needed.

The lowest dose of budesonide associated with appropriate therapeutic effect should be used in children, adolescents, and infants. Of particular concern in pediatric patients, budesonide, like other corticosteroids, may interfere with growth patterns, regardless of route of administration. Pediatric patients receiving any formulation of budesonide should be monitored closely for growth inhibition. Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients; therefore, growth should be routinely monitored during use.[33486] [34376] [31824] [34979] [52910] [57670] Other precautions in pediatric patients are related to hypothalamic-pituitary-adrenal (HPA) function and risk for HPA-axis suppression, which is generally low with inhaled budesonide, but must be monitored for carefully in pediatric patients on corticosteroids. Adrenal suppression and increased intracranial pressure have been reported with the use and/or withdrawal of systemic, intranasal, orally inhaled, and topical corticosteroids in pediatric patients.[44131] [51792] [58998] Budesonide respiratory inhalations have been evaluated for safety and efficacy in children and infants of varying ages, but the recommended ages for use vary by product. For nebulizer inhalation (Pulmicort Respules), the product is not approved in infants, but has been used off-label in infants as young as 3 months of age; efficacy in neonates has not been determined as limited trials have not shown benefit over systemic corticosteroids for indications such as prevention of bronchopulmonary dysplasia.[33486] [33594] [44927] [56029] The safety and efficacy of budesonide aerosol powder for inhalation (Pulmicort Flexhaler) has not been determined for pediatric patients less than 6 years of age.[34376] The safety and efficacy of rectal budesonide (e.g., Uceris) in pediatric patients has not been determined.[52910] Oral budesonide (e.g., Uceris, Ortikos) is safe and effective in pediatric patients 8 years and older with Crohn's disease.[34979] [64318] Nasal inhalations of budesonide (e.g., Rhinocort Aqua, Rhinocort Allergy) are safe and effective in children 6 years and older; however, prolonged administration requires careful monitoring by a health care provider.[31824] [59312] The safety and efficacy of oral budesonide (e.g., Tarpeyo) have not been established in pediatric patients.[67192]

Studies of pregnant women have not shown that inhaled budesonide increases the risk of abnormalities when administered during pregnancy.[31824] [33486] [34376] [46711] A review of Swedish registries of more than 2,000 births indicated that no increased risk for congenital malformations during early pregnancy with budesonide inhalation powder or solution.[46713] Despite adverse effects in animal studies, fetal harm appears remote. Corticosteroid treatment may not be necessary during pregnancy due to a natural increase in corticosteroid production; however, poorly controlled maternal asthma also poses risk to the mother and the fetus. Low-dose inhaled corticosteroids are considered first-line therapy for control of mild persistent asthma during pregnancy according to the National Asthma Education and Prevention Program (NAEPP) Asthma and Pregnancy Working Group; of the inhaled corticosteroids, more data are available for budesonide use in pregnancy. Data on the use of medium- to high-dose inhaled corticosteroid use during pregnancy are limited. However, dose titration may be considered for those with moderate to severe persistent asthma, preferably using budesonide. However, there are no data to indicate safety concerns with other inhaled corticosteroids, and maintaining a previously established treatment regimen may be more beneficial to the patient.[31822] Selection of any pharmacologic treatment for asthma control during pregnancy should include the specific needs of the patient, based on an individual evaluation, and consideration of the potential benefits or risks to the fetus. A position statement by the American College of Allergy, Asthma and Immunology also considers budesonide a good choice for pregnant women requiring high doses of inhaled steroids for effective asthma management.[46717] Limited published studies report on the use of oral budesonide in pregnant patients; however, the data are insufficient to inform a drug-associated risk of major birth defects and miscarriage. Oral budesonide products (e.g., Entocort EC, Ortikos, Uceris, Tarpeyo) have been teratogenic and embryocidal in animal studies. At subcutaneous budesonide doses that were 0.3 to 0.5 or 0.03 to 0.05 times the maximum recommended human dose (MRHD) in pregnant rats and rabbits, respectively, fetal loss, decreased pup weights, and skeletal anomalies occurred. There is a natural increase in endogenous corticosteroid production during pregnancy, and many women will require a lower exogenous dose or no corticosteroid treatment at all during pregnancy. Oral budesonide (e.g., Entocort EC, Ortikos, Uceris) products should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. According to the manufacturer of oral budesonide (e.g., Tarpeyo), IgA nephropathy in pregnancy is associated with adverse maternal outcomes, including increased rates of cesarean section, pregnancy-induced hypertension, pre-eclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including stillbirth and low birth weight. Hypoadrenalism may occur in an infant born to a mother receiving corticosteroids during pregnancy, and the infant should be carefully observed for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting.[34979] [52910] [64318] [67192]

Like other corticosteroids, budesonide is excreted into breast milk. Based on data from a small number (n = 8) of breast-feeding women taking inhaled dry powder budesonide 200 to 400 mcg twice daily, approximately 0.3 to 1% of the dose inhaled by the mother is available via breast milk to an exclusively breast-fed infant. Budesonide plasma concentrations obtained in five of the infants in this study about 140 minutes after maternal drug administration and 90 minutes after breast-feeding were below quantifiable levels.[33725] Low-dose inhaled corticosteroids are considered first line therapy for control of mild persistent asthma during pregnancy and lactation according to the National Asthma Education and Prevention Program (NAEPP) Asthma and Pregnancy Working Group. Due to greater availability of data, budesonide is considered the preferred agent in this population.[31822] The amount of inhaled budesonide excreted in breast-milk is minute, and infant exposure is negligible. Reviewers and an expert panel consider all inhaled corticosteroids acceptable to use during breast-feeding.[33723] [33724] [31822]. According to the manufacturer of oral budesonide (e.g., Entocort EC, Ortikos, Uceris), a decision should be made whether to discontinue nursing or to discontinue oral budesonide, taking into account the clinical importance of medication to the mother.[34979] [52910] [64318] According to the manufacturer of oral budesonide (e.g., Tarpeyo), breast-feeding is not expected to result in significant exposure of the infant to the drug; however, routine monitoring of linear growth in infants is recommended with chronic use of budesonide in the nursing mother.[67192] Single- and repeated-dose pharmacokinetic studies have shown that maximum plasma budesonide concentrations after a 9 mg oral daily dose are up to 10-times greater than the concentrations measured after inhaled doses of 400 to 800 mcg/day. Assuming that the coefficient of extrapolation between inhaled and oral doses is constant across all doses, it is possible that budesonide exposure to breast-feeding infants after maternal oral ingestion may be up to 10-times higher than exposure to infants after maternally inhaled budesonide. However, the oral bioavailability of budesonide is low (approximately 9%) and would be also be expected to be minimal in infants who ingest budesonide through breast milk.[34979] [52910] Budesonide rectal foam (e.g., Uceris Rectal) is likely to result in budesonide in human milk. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.[58166]

Although the risk of developing hypothalamic-pituitary-adrenal (HPA) suppression is very low with inhaled budesonide, patients should, nevertheless, be monitored for this possibility. Particular care is needed for patients who are transferred from systemic to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic to less systemically absorbed inhaled corticosteroids; abrupt discontinuation should be avoided. Patients previously maintained on doses equivalent to 20 mg/day or more of prednisone may be at increased risk. The transfer from systemic corticosteroid therapy to orally inhaled budesonide may also result in unmasking of allergies or other immunologic conditions, such as rhinitis, eczema, eosinophilia, conjunctivitis, or arthritis, that were previously controlled by treatment with systemic corticosteroids. After withdrawal from systemic therapy, a number of months are required for recovery of HPA-axis function. Symptoms attributable to acute corticosteroid withdrawal, such as adrenal suppression and increased intracranial pressure may occur. Adrenocortical function monitoring (plasma and urine cortisol levels and response to ACTH stimulation) may be required. In a 5 day study, 0 to 24 hour cortisol concentration suppression was 45% and 78% for oral budesonide 9 mg/day and prednisolone 20 mg/day, respectively. Switching from oral corticosteroids with higher bioavailability to oral budesonide should be undertaken with caution. Systemic oral steroid therapy, such as prednisolone, should be tapered when initiating oral budesonide.

If hypothalamic-pituitary-adrenal suppression occurs, patients will require systemic corticosteroids during periods of physiologic stress (e.g., trauma, surgery, infection especially gastroenteritis, or other conditions associated with electrolyte loss). Although inhaled or nebulized budesonide may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of corticosteroid systemically and does not provide mineralocorticoid activity. With the use of oral budesonide, supplementation with a systemic corticosteroid is recommended during physiologic stress. If surgery is required, patients should notify all health care providers that they have received corticosteroids within the last 12 months.

Glucocorticoids, such as budesonide, should be avoided in patients with Cushing's disease since they can produce or aggravate Cushing's syndrome. It is possible that systemic corticosteroid effects such as hypercortisolism may appear in a small number of patients receiving inhaled budesonide, particularly at higher doses. If features consistent with hypercorticism or Cushing's disease occur, the steroid should be reduced slowly, consistent with accepted procedures for management of symptoms and for tapering of systemic steroids.

Due to the inhibitory effects of glucocorticoids on wound healing, intranasal budesonide should be avoided in patients with a recent history of oral surgery or nasal surgery, nasal trauma, or nasal septal ulcers until their condition has healed. Intranasal budesonide overuse, improper use, or chronic use might lead to nasal septal perforation; patients who experience recurrent episodes of epistaxis (nosebleeds) or nasal septum discomfort while taking this medication should contact their prescriber for evaluation. If perforation occurs, the drug should be discontinued until healing is complete.

Detrimental effects on bone metabolism, such as osteoporosis are expected to be much lower with inhaled rather than systemically administered corticosteroids. Some patients receiving high-dose inhaled budesonide or oral budesonide may experience reduced bone mineral density and chronic use should be approached cautiously in patients with osteoporosis or risks for osteoporosis. Compounding risk factors include preexisting osteopenia, prolonged immobilization, family history of osteoporosis, tobacco smoking, malnutrition, and use of other medications that may reduce bone mass.[34376] [52910] [64318] [67192]

Although oral budesonide has weak mineralocorticoid properties, hypertension due to edema and electrolyte imbalance may occur. Prolonged administration of systemic glucocorticoids also can result in edema and hypertension. In a review of 93 studies of corticosteroid use, hypertension was found to develop 4 times as often in steroid recipients compared to control groups.[24362] Congestive heart failure can occur in susceptible patients. Monitor patients with hypertension for any unwanted effects of budesonide therapy.[34979] [52910] [64318] [67192]

Systemic corticosteroids, such as budesonide, should be used with caution in patients with psychosis, emotional instability, renal disease, diabetes mellitus or a family history of diabetes (due to risk of hyperglycemia), or a seizure disorder because the drug's pharmacologic actions can exacerbate these conditions. Monitor carefully those patients with peptic ulcer disease since oral corticosteroids in these patients can have untoward effects (exacerbate ulceration and GI perforation risks).[34979] [52910] [64318] [67192] Use caution in patients with thyroid disease. Patients with hyperthyroidism have an increased rate of corticosteroid elimination and may have a less than expected drug-effect, while those with hypothyroidism have decreased corticosteroid clearance and can have an exaggerated drug response.

Monitor for increased signs and/or symptoms of hypercorticism in all patients with mild to moderate hepatic disease receiving systemic corticosteroids. Patients who have moderate to severe hepatic impairment may be at an increased risk of hypercorticism and adrenal axis suppression due to an increased budesonide systemic exposure. For the oral delayed-release capsules (i.e, Entocort EC), it is recommended to consider reducing the oral dosage in patients with moderate hepatic impairment (Child-Pugh Class B) and avoiding use in severe hepatic impairment (Child-Pugh Class C); for the oral extended-release capsules (i.e, Ortikos), use should be avoided in patients with moderate to severe hepatic impairment (Child-Pugh Classes B and C); for the oral delayed-release capsules (i.e, Tarpeyo), it is recommended to monitor for increased signs and/or symptoms of hypercorticism in patients with moderate hepatic impairment (Child-Pugh Class B) and avoiding use in severe hepatic impairment (Child-Pugh Class C); for the extended-release tablets (i.e., Uceris) it is recommended to monitor for increased signs and/or symptoms of hypercorticism in patients with moderate or severe hepatic impairment.[34979] [52910] [64318] [67192]

Corticosteroids, like budesonide, should be used cautiously in patients with glaucoma or other visual disturbance or with a family history of glaucoma. Corticosteroids are well known to cause cataracts and can exacerbate glaucoma during long-term administration. Rare instances of glaucoma, increased intraocular pressure, and cataracts have been reported following the inhaled administration of corticosteroids. Patients receiving topical or systemic corticosteroids chronically should be periodically assessed for ocular effects.

Systemic glucocorticoids, like budesonide, should be used with caution in patients with myasthenia gravis who are being treated with anticholinesterase agents. Muscle weakness may be transiently increased during the initiation of systemic glucocorticoid therapy in patients with myasthenia gravis, necessitating respiratory support.[34979] [52910] [64318]

True corticosteroid hypersensitivity is rare, nevertheless patients who have demonstrated a prior hypersensitivity reaction to budesonide should not receive any form of budesonide. It is possible, though also rare, that such patients will display cross-hypersensitivity to other corticosteroids. It is advisable that patients who have a hypersensitivity reaction to any corticosteroid undergo skin testing, which, although not a conclusive predictor, may help to determine if hypersensitivity to another corticosteroid exists. Such patients should be carefully monitored during and following the administration of any corticosteroid.[27616]

There is no special precaution needed for the dosage of inhaled, rectal, or nasal budesonide in older adults.[34376] [59312] [58166] In general, oral budesonide dose selection for a geriatric patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.[34979] [52910] [64318] [67192] According to the Beers Criteria, systemic corticosteroids are considered potentially inappropriate medications (PIMs) for use in geriatric patients with delirium or at high risk for delirium and should be avoided in these patient populations due to the possibility of new-onset delirium or exacerbation of the current condition. The Beers expert panel notes that oral corticosteroids may be required for chronic conditions but should be prescribed in the lowest effective dose and for the shortest possible duration.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to the OBRA guidelines, the need for continued use of a glucocorticoid, with the exception of topical or inhaled formulations, should be documented, along with monitoring for and management of adverse consequences. Intermediate or longer-term use may cause hyperglycemia, psychosis, edema, insomnia, hypertension, osteoporosis, mood lability, or depression. Use caution with orally inhaled corticosteroids, such as budesonide, as these can cause throat irritation and oral candidiasis, particularly if the mouth is not rinsed after administration.[60742]