Budesonide

Steroid psychosis has been well described with oral glucocorticoids, however, our search of the literature did not identify an association between delirium and the combination of inhaled glucocorticoids and long-acting beta-agonists. We describe the occurrence of delirium with the combination of an inhaled glucocorticoid and bronchodilator. An elderly male described confusion and hallucinations within 1 week after initiation of budesonide/formoterol for chronic obstructive pulmonary disease. The combination inhaler was discontinued with resolution of symptoms. Several weeks later, the patient was hospitalized and restarted on the combination inhaler. The patient was alert and oriented on admission, however, confusion and hallucinations progressed throughout his hospital stay. The combination inhaler was discontinued and his confusion and hallucinations resolved by discharge. The temporal relationship of these events and a probable Naranjo association allows for reasonable assumption that the use of the budesonide/formoterol combination inhaler caused or contributed to the occurrences of delirium in this elderly patient. The onset of delirium was likely due to the systemic absorption of the glucocorticoid from lung deposition, complicated in an individual with several predisposing risk factors for delirium. Health care providers should be aware of this potential adverse drug reaction when prescribing inhaled medications to older patients at risk for delirium.

A 48-year-old woman with HIV infection developed Cushingoid features while she was taking ritonavir-boosted darunavir. Cushing's syndrome was confirmed due to the drug interaction between ritonavir and budesonide. Diagnosis of iatrogenic Cushing's syndrome in HIV-positive patients who are on ritonavir-boosted protease inhibitors (PIs) presents a clinical challenge due to similar clinical features of lipohypertrophy related to ritonavir-boosted PIs. Although this complication has been widely described with the use of inhaled fluticasone, the interaction with inhaled budesonide at therapeutic dose is not widely recognized.

To present two cases of iatrogenic Cushing syndrome caused by the interaction of budesonide, an inhaled glucocorticoid, with ritonavir and itraconazole, we present the clinical and biochemical data of two patients in whom diagnosis of Cushing syndrome was caused by this interaction. A 71-year-old man was treated with inhaled budesonide for a chronic obstructive pulmonary disease and itraconazole for a pulmonary aspergillosis. The patient rapidly developed a typical Cushing syndrome complicated by bilateral avascular necrosis of the femoral heads. Serum 8:00 AM cortisol concentrations were suppressed at 0.76 and 0.83 ug/dL on two occasions. The patient died 4 days later of a massive myocardial infarction. The second case is a 46-year-old woman who was treated for several years with inhaled budesonide for asthma. She was put on ritonavir, a retroviral protease inhibitor, for the treatment of human immunodeficiency virus (HIV). In the following months, she developed typical signs of Cushing syndrome. Her morning serum cortisol concentration was 1.92 ug/dL. A cosyntropin stimulation test showed values of serum cortisol of <1.10, 2.65, and 5.36 ug/dL at 0, 30, and 60 minutes, respectively, confirming an adrenal insufficiency. Because the patient was unable to stop budesonide, she was advised to reduce the frequency of its administration and eventually taper the dose until cessation. Clinicians should be aware of the potential occurrence of iatrogenic Cushing syndrome and secondary adrenal insufficiency due to the association of inhaled corticosteroids with itraconazole or ritonavir.

Oral budesonide is commonly used for the management of Crohn's disease given its high affinity for glucocorticoid receptors and low systemic activity due to extensive first-pass metabolism through hepatic cytochrome P450 (CYP) 3A4. Voriconazole, a second-generation triazole antifungal agent, is both a substrate and potent inhibitor of CYP isoenzymes, specifically CYP2C19, CYP2C9, and CYP3A4; thus, the potential for drug-drug interactions with voriconazole is high. To our knowledge, drug-drug interactions between voriconazole and corticosteroids have not been specifically reported in the literature. We describe a 48-year-old woman who was receiving oral budesonide 9 mg/day for the management of Crohn's disease and was diagnosed with fluconazole-resistant Candida albicans esophagitis; oral voriconazole 200 mg every 12 hours for 3 weeks was prescribed for treatment. Because the patient experienced recurrent symptoms of dysphagia, a second 3-week course of voriconazole therapy was taken. Seven weeks after originally being prescribed voriconazole, she came to her primary care clinic with elevated blood pressure, lower extremity edema, and weight gain; she was prescribed a diuretic and evaluated for renal dysfunction. At a follow-up visit 6 weeks later with her specialty clinic, the patient's blood pressure was elevated, and her physical examination was notable for moon facies, posterior cervical fat pad prominence, and lower extremity pitting edema. Iatrogenic Cushing syndrome due to a drug-drug interaction between voriconazole and budesonide was suspected, and voriconazole was discontinued. Budesonide was continued as previously prescribed for her Crohn's disease. On reevaluation 2 months later, the patient's Cushingoid features had markedly regressed. To our knowledge, this is the first published case report of iatrogenic Cushing syndrome due to a probable interaction between voriconazole and oral budesonide. In patients presenting with Cushingoid features who have received these drugs concomitantly, clinicians should consider the potential drug interaction between these agents, and the risks and benefits of continued therapy must be considered.

For more Interactions (Complete) data for Budesonide (11 total), please visit the HSDB record page.

Long term therapy with budesonide has not been linked to elevations in serum enzyme levels, and in clinical trials rates of ALT elevations were similar with budesonide as with placebo treatment. In controlled trials, there were no reported cases of clinically apparent liver injury associated with its use. Unlike conventional systemically administered corticosteroids, budesonide has not been linked to episodes of reactivation of hepatitis B. Budesonide has been used in severe autoimmune liver diseases without evidence that it causes worsening of liver injury. Because it can improve serum aminotransferase elevations in patients with autoimmune hepatitis, its withdrawal may be followed by rebound elevations as also occurs with conventional corticosteroid therapy. In addition, there has been a single case report of acute serum aminotransferase elevations during budesonide therapy that resolved when the drug was stopped, but documentation was limited and the patient was on multiple other potentially hepatotoxic drugs.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 120(SRC), determined from a log Kow of 3.20(2) and a regression-derived equation(3), indicates that budesonide is expected to have high mobility in soil(SRC). Volatilization of budesonide from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.3X10-13 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Budesonide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 8.8X10-15 mm Hg at 25 °C(SRC), determined from a fragment constant method(3). Biodegradation data in soil were not available(SRC, 2015).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 120(SRC), determined from a log Kow of 3.20(2) and a regression-derived equation(3), indicates that budesonide is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(4) based upon an estimated Henry's Law constant of 1.3X10-13 atm-cu m/mole(SRC), developed using a fragment constant estimation method(5). According to a classification scheme(6), an estimated BCF of 60(SRC), from its log Kow(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation data in water were not available(SRC, 2015).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), budesonide, which has an estimated vapor pressure of 8.8X10-15 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase budesonide may be removed from the air by wet and dry deposition(SRC). Budesonide contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

IDENTIFICATION AND USE: Budesonide (trade names: Rhinocort, MMX) is a prescription medication approved for the treatment of allergic rhinitis (Rhinocort nasal spray) and mild to moderate Crohn's disease (MMX, enteric coated capsules). HUMAN EXPOSURE AND TOXICITY: Patch tests have indicated that budesonide can produce delayed allergic reactions, and atopic dermatitis. In cases of inhalational exposure, periorificial dermatitis has been reported. In cases of oral administration, Candida albicans esophagitis, dysphagia, elevated blood pressure, lower extremity edema, and weight gain have been reported, although some of these adverse events may have been the result of a drug interaction with voriconazole. Epidemiological studies have found an increased risk of pneumonia, cardiac dysrhythmias, cataracts, and fractures associated with inhaled budesonide use. Additional epidemiological studies have found that budesonide inhalation during pregnancy may be a risk factor for offspring endocrine and metabolic disturbances. Low birth weight has also been reported. In children taking budesonide for persistent asthma, slower linear growth, slow weight gain, and slow skeletal maturation have also been observed. Localized Candidal infections of the nose and pharynx has been reported during intranasal budesonide therapy. Patients may be at an increased risk for certain infections, such as Varicella (chickenpox). In children and adolescents, administration of budesonide may cause growth suppression. It may also cause acute or delayed hypersensitivity reactions. Hypoadrenalism may occur in infants of mothers receiving corticosteroid therapy during pregnancy. ANIMAL STUDIES: In carcinogenicity studies, hepatocellular tumors and gliomas have been observed in rats that received oral budesonide. In female rats that received budesonide subcutaneously, a decrease in prenatal viability and viability of pups during pregnancy and lactation was observed. Pyloric hyalinization was detected in mice that received budesonide orally.

The potential for acute toxicity is rare, but overdosing of budesonide for a prolonged period may result in systemic toxicity such as hypercortisolism.

The Koc of budesonide is estimated as 120(SRC), using a log Kow of 3.20(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that budesonide is expected to have high mobility in soil(SRC).

/HUMAN EXPOSURE STUDIES/ Two readings of patch test reactions were recommended. To evaluate the outcome of a second patch test reading of TRUE Test allergens on D6/7 in relation to negative or doubtful reactions on D3/4. This was a retrospective investigation of patch test data from January 1992 to October 2011 from consecutive eczema patients tested with the TRUE Test panels. In the period of nearly 20 years, a total of 9997 patients were tested. The total number of positive reactions to the 29 allergens was 6509; 4.4% were positive on D6/7 and negative on D3/4; and 9.1% were positive on D6/7 after a doubtful (+) reaction on D3/4. Neomycin was the most frequent allergen giving delayed positive reactions (57%), followed by budesonide (42%) and hydrocortisone-17-butyrate (31%). A total of 4.4% of positive TRUE Test reactions would be missed, and 9.1% might be missed, if only one reading was performed on D3/4. The results emphasize that many doubtful reactions at D3/4 may develop into positive reactions at a later reading. This may have important implications for evaluation of the clinical relevance of the test result.

/HUMAN EXPOSURE STUDIES/ Until recently, it was thought that in patients with atopic dermatitis (AD), contact hypersensitivity phenomenon occurs less frequently than in the general population because of the impaired cellular immune response. The aim of this study was to evaluate the incidence of contact dermatitis in the population of patients with AD. A total of 39 patients with clinical diagnosis of AD during remission were patch tested with 28 European Baseline Series allergens and 8 corticosteroids allergens in different concentrations and media. Nineteen (48%) patients had an allergic reaction to at least 1 European Standard Series allergen, and 5 (12.8%) patients had an allergic reaction to at least 1 corticosteroid. The most common allergens giving positive results were nickel sulfate (28.2%), potassium dichromate (20.5%), cobalt chloride (12.8%), and phenylenediamine, budesonide, betamethasone, clobetasol, and dexamethasone (7.7% each). This study shows that allergic contact hypersensitivity is common among patients with AD and affects up to 40% of cases.

/CASE REPORTS/ We report a case of periorificial dermatitis caused by suboptimal inhalation of budesonide for asthma. The initial skin lesions presented in the eye surroundings, leading to diagnostic difficulties and treatment of presumed chalazion and staphylococcal folliculitis. After several months, the patient developed perioral papules and pustules and was diagnosed with periorificial dermatitis. He was efficiently treated with topical metronidazole and oral erythromycin.

/CASE REPORTS/ We report the case of a 41-year-old nonatopic woman with a previous history of eczematous reaction due to hydrocortisone who suffered worsening of her perennial rhinitis in association with perinasal dermatitis from the use of budesonide in nasal spray form, and stomatitis and pharyngitis due to budesonide in a bronchial inhaler. Patch tests with a series of 25 corticosteroids, some of them at different concentrations and in different vehicles, were positive to tixocortol pivalate, hydrocortisone, budesonide, prednisolone, hydrocortisone butyrate propionate, triamcinolone acetonide, and fluocinolone acetonide. For some of them, a 1% solution in ethanol gave a positive reaction when a 20% mixture in petrolatum did not. Like other authors, we suggest that some multiple positives may represent sensitization to several steroids independently, true cross-reactions, or both, and that ethanol is a better vehicle than petrolatum.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Budesonide

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

An estimated BCF of 60 was calculated in fish for budesonide(SRC), using a log Kow of 3.20(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC).

The Henry's Law constant for budesonide is estimated as 1.3X10-13 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that budesonide is expected to be essentially nonvolatile from water and moist soil surfaces(2). Budesonide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 8.8X10-15 mm Hg(SRC), determined from a fragment constant method(3).

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including budesonide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

MEDICATION

Anti-Inflammatory Agents; Bronchodilator Agents; Glucocorticoids

Use (kg; approx.) in Germany (2009): >250

11beta,16alpha,17,21-Tetrahydroxypregna-1,4-diene-3,20-dione is converted to the 16,17-acetal with butyraldehyde.

Preparation: R. L. Brattsand et al., German patent 2323215; eidem, USA patent 3929768 (1973, 1975 both to Bofors).

Table: Budesonide Preparations [Table#8274]

Nasal: Suspension, for intranasal use only: 32 ug/metered spray, Rhinocort Aqua Nasal Spray (AstraZeneca)

Table: Budesonide Combination Preparations [Table#8275]

Trade name: Budecort, Entocort, Pulmicort (AstraZeneca, worldwide); Budecort (Astellas, Germany); Budenase (Cipla, Hong Kong, Malaysia); Budenofalk (Falk, Europe, Asia); Budiair (Chiesi, Greece, Italy, Germany); Inflammide (Boehringer Ingelheim, Czech Republic, Singapore, Malaysia, South Africa, Thailand, Indonesia); Miflonide (Novartis, Europe, Brazil, Venezuela).

For more Formulations/Preparations (Complete) data for Budesonide (6 total), please visit the HSDB record page.