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Pharmacotherapeutic group: Inhalation drugs for obstructive airway diseases. ATC-code: R03BA02.
Pharmacology: PULMICORT is a corticosteroid for inhalation use in the treatment and prophylaxis of asthma.
Studies in animals and humans have shown an advantageous ratio between topical anti-inflammatory activity and systemic glucocorticoid effect over a wide dose range. This is explained by the extensive first pass hepatic degradation of budesonide after systemic absorption, approximately 85 - 90%, in combination with the low potency of formed metabolites.
Budesonide is approximately twice as potent as beclomethasone dipropionate as shown in the skin blanching test for anti-inflammatory activity of topical steroids in humans. Budesonide has, however, less systemic effect than beclomethasone dipropionate, as measured by depression of morning plasma cortisol and effect on differential WBC count. The improved ratio of topical anti-inflammatory activity to systemic effect of budesonide is due to high glucocorticoid receptor affinity combined with a high first pass metabolism and a short half-life.
Doses of 0.8 mg have been found to suppress plasma cortisol levels and urinary cortisol secretion. A single inhalation of 3.2 mg budesonide was found to suppress plasma cortisol levels to a degree similar to 10 mg oral prednisolone.
Budesonide has been shown to counteract the mainly "IgE" but not the mainly "IgG" mediated lung anaphylaxis in guinea pigs. Pre-treatment for one to four weeks with inhaled budesonide 1 mg daily in asthmatic patients inhibited the immediate bronchial reaction to allergen challenge in a time-related manner; the late reaction is inhibited after one week of inhaled treatment.
Inhaled budesonide pre-treatment for 2 to 4 weeks has also been shown to reduce non-specific bronchial hyper-responsiveness in asthmatic patients to both direct (histamine, methacholine) and indirect (exercise) provocative stimuli in a time-related manner.
Budesonide did not potentiate β-receptor-mediated bronchodilation and did not affect theophylline-induced relaxation of respiratory airway smooth muscle in guinea pigs. In man, single oral inhalations of up to 1.6 mg budesonide produced mild bronchodilation. This effect is maximal at 6 hours after inhalation with a duration of 12 hours.
Clinical - croup: A number of studies in children with croup have compared Pulmicort Respules with placebo. Examples of representative studies evaluating the use of Pulmicort Respules for the treatment of children with croup are given as follows.
Efficacy in children with mild to moderate croup: A randomised, double-blind placebo-controlled trial in 87 children (aged 7 months to 9 years), admitted to hospital with a clinical diagnosis of croup, was conducted to determine whether Pulmicort Respules improves croup symptom scores or shortens the duration of stay in hospital. An initial dose of Pulmicort Respules (2 mg) or placebo was given followed by either Pulmicort Respules 1 mg or placebo every 12 hours. Pulmicort Respules statistically significantly improved croup score at 12 and 24 hours and at 2 hours in patients with an initial croup symptom score above 3. There was also a 33% reduction in the length of stay.
Efficacy in children with moderate to severe croup: A randomised, double-blind, placebo-controlled study compared the efficacy of Pulmicort Respules and placebo in the treatment of croup in 83 infants and children (aged 6 months to 8 years) admitted to hospital for croup. Patients received either Pulmicort Respules 2 mg or placebo every 12 h for a maximum of 36 h or until discharge from hospital. The total croup symptom score was assessed at 0, 2, 6, 12, 24, 36 and 48 hours after the initial dose. At 2 hours, both the Pulmicort Respules and placebo groups showed a similar improvement in croup symptom score, with no statistically significant difference between the groups. By 6 hours, the croup symptom score in the Pulmicort Respules group was statistically significantly improved compared with the placebo group, and this improvement versus placebo was similarly evident at 12 and 24 hours.
Acute Exacerbations of Asthma: Evidence from the 10 key paediatric studies showed that a daily dose nebulised budesonide dose of 1.5 mg to 4 mg is effective. All doses investigated in the key paediatric studies, either as a replacement for systemic corticosteroids or in addition to systemic corticosteroids, were consistent with the proposed label, with single doses up to 2 mg and maximum daily doses of 4 mg. Daily doses up to 6 mg may be considered in children aged 5 years or over. The use of this higher dose of nebulised budesonide in paediatric patients is supported by efficacy and safety data from AstraZeneca-sponsored Study 04-9305. The safety data in these studies were consistent with the know safety profile of budesonide in patients with asthma, therefore there was no evidence of additional safety concerns due to short-term use at an elevated dose.
In the clinical studies supporting the efficacy and safety of nebulised budesonide to treat acute exacerbations of asthma, duration of nebulised budesonide treatment was typically either less than 1 day or up to 3-5 days, although some studies had longer duration. A 10-day limit for treatment of exacerbations in paediatric and adult patients is proposed to provide appropriate treatment duration for acute exacerbations of asthma at the appropriate nebulised budesonide doses. Nebulised budesonide is indicated for the treatment of bronchial asthma with approved posology for maintenance treatment, and treatment can therefore continue beyond 10 days at these lower doses.
Key adult study Sun et al 2012 investigated total daily doses of 2 mg (1 mg BID), 4 mg (2 mg BID) and 8 mg (2 mg four times daily) in adult patients with severe acute exacerbations of asthma. In this study, a total daily dose of 8 mg was as effective as systemic corticosteroids (intravenous methylprednisolone 40 mg once daily) at all time points assessed, while total daily dose of 4 mg was as effective as systemic corticosteroids from 72 hours after the start of treatment. Treatment with systemic corticosteroids in this study resulted in decreases in mean cortisol concentrations and increases in mean blood glucose Concentrations, which were not reported with budesonide treatment. The results for the 8 mg daily dose of nebulised budesonide support the inclusion of this dose in the proposed label for similar efficacy to systemic corticosteroids with a better safety profile. A total daily dose of 20 mg (five 4 mg doses in 24 hours) was investigated in the key efficacy study in adult patients (Study 04-3022), dosing was therefore consistent with the maximum single dose proposed for the treatment of acute exacerbations of asthma in adults, although the total daily dose was higher. In this study, treatment with nebulised budesonide led to improvements in lung function in patients with asthma exacerbations. These improvements were comparable to those in patients receiving a high dose of systemic corticosteroid used (160 mg prednisolone, as well as a lower 30 mg dose). Crucially, there was no evidence of additional safety concerns due to short-term use of elevated doses of nebulised budesonide in this study.
Daily nebulised budesonide doses between 4 mg and 8 mg have also been shown to be efficacious and well-tolerated in the management of exacerbations of chronic obstructive pulmonary disease.
Following are other new supporting data for AE Asthma: Study by Bahrami et al. (2020) on subjects aged 2-12 years old with acute asthma (n=80) that treated with budesonide or placebo, and standard therapy (oxygen, beta-2 agonist, hydrocortisone), showed subjects without symptoms after 48 hours in percentage as follows: Wheezing score: 95% vs. 17.5% (p<0.001); Cough score: 100% vs. 10% (p<0.001); Distress score: 100% vs. 87.5% (p=0.021).
Study by Abood et al. (2021) on subject aged 1-12 years old with mild to moderate exacerbation asthma (n=100 that treated with budesonide + salbutamol or salbutamol showed: The decrease of pulmonary index score after 30 minutes: 35.9% vs 22.1% (p=0.001); Duration of emergency department stay (minutes): 63.30±21.71 vs. 77.40±16.13 (p=0.001).
Local study by Susanti et al. (2002) on subjects aged 12-65 years old with severe acute asthma (n=64) that treated with budesonide + terbutaline or metilprednisolon + terbutaline showed: Wheezing improvement: 81.3% vs. 62.5%; Improvements in peak expiratory flow (APE) 120 min: 66.9 ± 18.2% vs. 64.8 ± 18.8%; Reported side effects are palpitations and dryness in the mouth, with the highest percentage at minute 60 is 68.8% vs. 75%, p>0.05; and 59.4% vs. 21.9%, p<0.005, respectively.
Exacerbations of COPD: Several studies on nebulised budesonide, 4-8 mg/day has shown to effectively treat exacerbations of COPD. The efficacy of Budesonide was evaluated in an open label, randomised, comparative study in 78 hospitalised patients with acute exacerbations of COPD in two parallel groups receiving nebulised budesonide (n=37) 4 mg/day (2 mg twice daily) or intravenous infusion of prednisolone 120-180 mg/day (n=41) for 7-14 days. Patients treated with nebulized budesonide or prednisolone showed similar improvements in FEV1, SpO2 (saturation as measured by pulse oximetry) and symptoms (CAT score).
In a multi-center randomised controlled, single-blind study involving 410 patients with acute exacerbations of COPD, patients were treated with nebulised budesonide 6 mg/day (2 mg three times/day); or intravenously injected methylprednisolone (40 mg/day) for 10 days. Clinical efficacy of nebulised budesonide in comparison to systemic methylprednisolone as measured by FEV1, PaCo2 and symptoms (CAT score) was comparable, while PaO2 improved more in the methylprednisolone group. In a double-blind randomised placebo-controlled study involving 199 patients with acute exacerbations of COPD, patients were treated with nebulised budesonide 8 mg/day (2 mg four times a day (n=71) or 30 mg oral prednisolone every 12 hours (n-62) or placebo (n=66) for 3 days. Improvement in post bronchodilator FEV1 compared to placebo was 0.10 L for budesonide and 0.16 L for prednisolone; the difference between the active treatments was not statistically significant. The proportion of patients showing clinical improvement in postbronchodilator FEV1 of at least 0.15 L was greater in the nebulised budesonide group (34%) and the prednisolone group (48%) than in the placebo group (18%). The differences were statistically significant for both active treatments versus placebo (p < 0.05) but not between the active treatments.
Addition of indication for treatment of exacerbating chronic obstructive pulmonary disease (COPD) is also supported by study conducted by Zhang et al. (2020) with randomized design in subjects with acute exacerbation of chronic obstructive pulmonary disease (n=321) treated with budesonide with dose of 4mg/day (1 mg Q6h) or 8 mg/day (2 mg Q6h) or 8 mg/day (4 mg Q12h), showed improvement based on observation at 5 days after therapy, as follows: PaO2 (mmHg): 72.1 ± 10.7 vs. 74.7 ± 14.8 vs. 76.2 ± 16.3; CAT score: 9.5 ± 3.3 vs. 9.0 ± 4.7 vs. 8.2±3.2; FEV1% predicted: 58.6 ± 8.3 vs. 57.3 ± 8.5 vs. 61.7 ± 8.1.
Pharmacokinetics: Approximately 10% of the discharged dose of PULMICORT aerosol is deposited in the lungs.
The volume of distribution of budesonide in adult man is approximately 300 L and in children is 3.1 to 4.8 L/kg indicating a high tissue affinity. Plasma protein binding is 88.3 ± 1.5% in humans.
In adults, the plasma half-life following inhalation via aerosol was 2.0 ± 0.2 hours and in children 1.5 hour with peak plasma levels occurring immediately after administration.
Negligible biotransformation was observed in human lung and serum preparations.
PULMICORT is 90% inactivated on first pass through the liver via metabolism to more polar metabolites with a more than 100-fold lower glucocorticosteroid systemic activity than the parent compound.
In human volunteers who inhaled titrated budesonide, 31.8 ± 7.5% of the discharged dose was recovered in urine and 15.1 ± 4.3% in faeces (0 - 96 h). Plasma clearance of unchanged budesonide was calculated to be 84 L/h in adults and 1.5 to 2 L/h/kg in children.
Toxicology: Carcinogenicity & mutagenicity: The carcinogenic potential of budesonide has been evaluated in mouse and rat at oral doses up to 200 and 50 μg/kg/day, respectively. No oncogenic effect was noted in the mouse. One study indicated an increased incidence of brain gliomas in male Sprague-Dawley rats given budesonide, however, the results were considered equivocal. Further studies performed in male Sprague-Dawley and Fischer rats showed that the incidence of gliomas in the budesonide-treated rats was low and did not differ from that in the reference glucocorticoid groups or the controls. It has been concluded that treatment with budesonide does not increase the incidence of brain tumours in the rat.
In male rats dosed with 10, 25 and 50 μg/kg/day, those receiving 25 and 50 μg/kg/day showed an increased incidence of primary hepatocellular tumours. This was observed in all three steroid groups (budesonide, prednisolone, triamcinolone acetonide) in a repeat study in male Sprague-Dawley rats, thus, indicating a class effect of corticosteroids.
The mutagenic potential of budesonide was evaluated in 6 different test systems. No mutagenic or clastogenic effects of budesonide were found.
