Pulmicort

Budesonide.

One single dose unit contains 0.5 mg or 1.0 mg budesonide per 2 mL.
The active ingredient, budesonide, is a non-halogenated glucocorticoid structurally related to 16α hydroxyprednisolone. The chemical name is 16α, 17α - 22R, S-propylmethylenedioxy-pregna-1, 4-diene-11β, 21-diol-3, 20-dione; MW 430.5.
Budesonide is a white to off-white powder, freely soluble in chloroform, sparingly soluble in ethanol and practically insoluble in water and heptane. Budesonide melts with decomposition between 224°C and 231.5°C.
Excipients/Inactive Ingredients: Disodium edetate, sodium chloride, polysorbate 80 (E433), anhydrous citric acid (E330), sodium citrate (E331), water for injection and nitrogen.

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.

Treatment of bronchial asthma; Treatment of moderate to severe acute laryngotracheobronchitis (croup) in infants and children.
Pulmicort nebuliser suspension is indicated in patients with: Treatment of acute exacerbations asthma.
Treatment of exacerbations of chronic obstructive pulmonary disease (COPD).

PULMICORT RESPULES should be administered from a suitable nebuliser. The dose delivered to the patient varies between 40 - 60% of the nominal dose depending on the nebulising equipment used. The nebulisation time and the dose delivered are dependent on flow rate, volume of nebuliser chamber and volume fill. A suitable fill for most nebulisers is 2 - 4 mL.
Some sedimentation may occur during storage of PULMICORT RESPULES. If this does not readily resuspend completely upon shaking, the respules should be discarded.
Bronchial Asthma: Dosage initially, or during periods of severe asthma, or while reducing oral corticosteroids: Adults, Children 12 years and older: 1 - 2 mg twice daily.
Children age 3 months - 12 years: 0.5 - 1 mg twice daily.
Maintenance: The maintenance dose should be individualised and should be the lowest dose, which keeps the patient symptom-free. Recommended doses are: Adults: 0.5 - 1 mg twice daily.
Children age 3 months - 12 years: 0.25 - 0.5 mg twice daily.
Acute Laryngotracheobronchitis (Croup): In infants and children with croup the usual dose is 2 mg of nebulised budesonide given as a single administration of Pulmicort Respules.
Acute Exacerbations of Asthma: Adults: Daily recommended dose is 4 to 8 mg and can be divided into 1 to 4 administrations.
In very severe cases the dose may be further increased. Maximum dose at one occasion should not exceed 4 mg. Treatment with nebulized Pulmicort for acute exacerbations can be continued until clinical improvement, but for no longer than 10 days.
Children (aged 6 months to 17 years): daily recommended dose is 1.5 to 4 mg, doses up to 6 mg can be considered in children 5 years or above. Daily dose can be divided into 1 to 4 administrations. Maximum dose at one occasion should not exceed 3 mg. Treatment with nebulized Pulmicort for acute exacerbations can be continued until clinical improvement, but for no longer than 10 days.
In both adults and children, nebulised budesonide is not a substitute for systemic corticosteroids in life threatening asthma. Treatment for exacerbations may be followed by ICS (Inhaled Corticosteroids) containing therapy in appropriate doses using suitable delivery systems.
Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): Patients should be treated with daily doses of 4 to 8 mg of PULMICORT nebulizer suspension, divided into 2 to 4 administrations, until clinical improvement but for no longer than 10 days.
Onset of effect: Following inhaled administration of Pulmicort Nebulizer Suspension for the treatment of exacerbations of COPD the time to symptom improvement is comparable to administration of systemic corticosteroids.
Clinical Management: Patients - not oral corticosteroid dependent: Treatment with the recommended doses of PULMICORT usually gives a therapeutic effect within 10 days.
In patients with excessive mucus secretion in the bronchi, an initial short course (about 2 weeks) of an oral corticosteroid, commencing with a high dose and gradually reducing, should be given in addition to PULMICORT.
Patients - oral corticosteroid dependent: Transfer of patients dependent on oral corticosteroids to PULMICORT requires special care because of slow normalisation of the disturbed hypothalamic-pituitary-adrenal function caused by extended treatment with oral corticosteroids (see Oral Corticosteroid usage and Potential systemic effects of inhaled corticosteroids - HPA axis suppression and adrenal insufficiency under PRECAUTIONS).
When PULMICORT treatment is initiated, the patient's asthma should be in a relatively stable phase. The dose of oral corticosteroid should then be reduced gradually to the lowest possible level. The dose of PULMICORT should not be changed while the patient remains on oral corticosteroids.
In many cases, it may be possible to completely replace the oral corticosteroid with inhaled PULMICORT. In other patients, a low oral steroid maintenance dose may be necessary. Some patients may experience uneasiness during the withdrawal of oral corticosteroids due to the decreased systemic corticosteroid effect. The physician may need to actively support the patient and to stress the reason for the PULMICORT treatment.
The length of time needed for the body to regain sufficient natural corticosteroid production is often extended and may be as long as 12 months. Transferred patients should carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress, such as severe infection, trauma or surgery. During such times, it may be necessary to give additional oral corticosteroids.
During transfer from oral therapy to PULMICORT, a lower systemic steroid action is experienced. Earlier allergic symptoms may recur (e.g. rhinitis, eczema, conjunctivitis) or patients may suffer from tiredness, headache, muscle and joint pain, lassitude and depression or occasionally nausea and vomiting. In these cases, further medical support may be required.

Symptoms: In most cases, occasional overdosing will not produce any obvious symptoms but will decrease the plasma cortisol level and increase the number and percentage of circulating neutrophils. The number and percentage of lymphocytes and eosinophils will decrease concurrently. Habitual overdosing may cause hypercorticism and hypothalamic-pituitary-adrenal suppression.
Treatment: Withdrawing PULMICORT or decreasing the dose will abolish these effects, although the normalization of the HPA-axis may be a slow process.

Hypersensitivity to budesonide or any other ingredients.

Bronchospasm: PULMICORT is not indicated for rapid relief of bronchospasm. PULMICORT is therefore not suitable as sole therapy for the treatment of status asthmaticus or other acute exacerbations of asthma where intensive measures are required.
If patients find short-acting bronchodilator treatment ineffective, or they need more inhalations than usual, medical attention must be sought. This indicates a worsening of the underlying conditions and warrants a reassessment of the therapy.
Oral corticosteroid usage: Particular care is needed in patients who are being transferred from oral corticosteroids to PULMICORT, since they may remain at risk of impaired adrenal function for some considerable time (see Potential systemic effects of inhaled corticosteroids: HPA axis suppression and adrenal insufficiency as follows). These patients should be instructed to carry an appropriate warning card (see Clinical Management: Patients - Oral corticosteroid dependent under Dosage & Administration).
Patients previously receiving high doses of systemic steroids may regain earlier allergic symptoms such as rhinitis and eczema when transferred from oral therapy to PULMICORT due to the reduced systemic steroid effect of budesonide (see Clinical Management: Patients - Oral corticosteroid dependent under Dosage & Administration).
Potential systemic effects of inhaled corticosteroids: Inhaled steroids are designed to direct glucocorticoid delivery to the lungs in order to reduce overall systemic glucocorticoid exposure and side effects. However, inhaled steroids may have adverse effects; possible systemic effects of inhaled steroids include depression of the HPA axis, reduction of bone density, cataracts and glaucoma, and retardation of growth rate in children. In steroid-dependent patients, prior systemic steroid usage may be a contributing factor (see Oral corticosteroid usage as previously mentioned), but such effects may occur amongst patients who use only inhaled steroids regularly.
HPA axis suppression and adrenal insufficiency: Dose-dependent HPA axis suppression (as indicated by 24 hour urinary and/or plasma cortisol AUC) has been observed with inhaled budesonide, although the physiological circadian rhythms of plasma cortisol were preserved. This indicates that the HPA axis suppression may represent a physiological adaptation in response to inhaled budesonide, not necessarily adrenal insufficiency. The lowest dose that results in clinically relevant adrenal insufficiency has not been established. Very rare cases of clinically relevant adrenal dysfunction have been reported in patients using inhaled budesonide at recommended doses.
Particular care is needed in patients who are being transferred from oral corticosteroids to PULMICORT, since they may remain at risk of impaired adrenal function for some considerable time (see Oral corticosteroid usage as previously mentioned). Patients who have required high dose emergency corticosteroid therapy, prolonged treatment at the highest recommended dose of inhaled corticosteroids or patients administering concomitant medication metabolised by CYP3A4 (see INTERACTIONS) may also be at risk. These patients may exhibit signs and symptoms of adrenal insufficiency when exposed to severe stress such as trauma, surgery, infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Monitoring for signs of adrenal dysfunction is advisable in these patient groups. For these patients, additional systemic glucocorticosteroid cover should be considered during periods of stress, severe asthma attack or elective surgery.
Bone density: Whilst corticosteroids may have an effect on bone mass at high doses, long term follow up (3-6 years) studies of budesonide treatment in adults at recommended doses have not demonstrated a negative effect on bone mass compared to placebo, including one study conducted in patients with a high risk of osteoporosis. The lowest dose that does affect bone mass has not been established.
Bone mineral density measurements in children should be interpreted with caution as an increase in bone area in growing children may reflect an increase in bone volume. In three large medium to long-term (12 months - 6 years) studies in children (5 - 16 years), no effects on bone mineral density were observed after treatment with PULMICORT (189 - 1322 μg/day) compared to nedocromil, placebo or age matched controls. However, in a randomised 18 month study (n=176; 5-10 years), bone mineral density was significantly decreased by 0.11 g/cm² (p=0.023) in the group treated with inhaled budesonide via Turbuhaler compared with the group treated with inhaled disodium cromoglycate. The dose of budesonide was 400 μg twice daily for 1 month, 200 μg twice daily for 5 months and 100 μg twice daily for 12 months and the dose of disodium cromoglicate 10 mg three times daily. The clinical significance of this result remains uncertain. Should not be used as a long term treatment in children.
Growth: Long term studies show that children treated with inhaled budesonide ultimately achieve adult target height. However, an initial reduction of growth velocity (approximately 1 cm) has been observed and is generally within the first year of treatment. Rare individuals may be exceptionally sensitive to inhaled corticosteroids. Height measurements should be performed to identify patients with increased sensitivity. The potential growth effects of prolonged treatment should be weighed against the clinical benefit. To minimise the systemic effects of inhaled corticosteroids, each patient should be titrated to his/her lowest effective dose (see DOSAGE & ADMINISTRATION).
Infections and tuberculosis: High doses of glucocorticosteroids may mask some signs of existing infection and new infections may appear during their use. Special care is needed in patients with active or quiescent pulmonary tuberculosis or fungal, bacterial or viral infections of the respiratory system.
Hepatic function: Decreased liver function may affect the ability to eliminate budesonide. This may be clinically relevant in patients with severely compromised liver function.
Positive pressure delivery systems: Respiratory drugs should not be used with positive pressure delivery systems (e.g. IPPB) in pulmonary conditions involving pneumothorax, air cysts or mediastinal emphysema unless special drainage is performed.

Pregnancy: Administration during pregnancy should be avoided unless there are compelling reasons. In pregnant animals, administration of budesonide causes abnormalities of foetal development. The relevance of this finding to man has not been established.
Lactation: Budesonide is excreted in breast milk. However, at therapeutic doses of PULMICORT RESPULES no effects on the suckling child are anticipated. PULMICORT RESPULES can be used during breast feeding.

PULMICORT is generally well tolerated. Most adverse reactions have been mild and of a local character. Systemic effects and oropharyngeal complications caused by budesonide were found to be dose dependent.
Clinical signs of steroid excess were present in 50% of patients (n=10) taking 1.6 mg or more daily of budesonide alone for long periods.
Clinical trials, literature reports and post-marketing experience suggest that the following adverse drug reactions may occur: Common (more than 1%): Nose and throat: hoarseness; sore, mild irritated throat; irritation of the tongue and mouth; dry mouth; oral candidiasis.
Respiratory: cough.
Uncommon (less than 1%): Nose and throat: irritation of the larynx; bad taste.
Gastrointestinal: diarrhea; nausea.
Hypersensitivity reactions: Immediate and delayed hypersensitivity reactions such as skin reactions (e.g. urticaria, rash, dermatitis), bronchospasm, angioedema and anaphylactic reaction.
Central nervous system: headache; lightheadedness; thirst; tiredness.
Metabolic and nutritional disorders: weight gain.
If oropharyngeal candidiasis develops, it may be treated with appropriate anti-fungal therapy whilst still continuing with PULMICORT therapy. The incidence of candidiasis can generally be held to a minimum by having patients rinse their mouth with water after each inhalation.
In rare cases signs or symptoms of systemic glucocorticosteroid effect, including hypofunction of the adrenal gland and reduction of growth velocity, may occur with inhaled glucocorticosteroids, probably depending on dose, exposure time, concomitant and previous steroid exposure, and individual sensitivity.
Inhaled steroids may have adverse effects in higher than recommended doses; possible systemic effects of inhaled steroids include depression of the HPA axis, reduction of bone density and retardation of growth rate in children (see Potential systemic effects of inhaled corticosteroids under PRECAUTIONS).
Reduction in growth velocity has been reported in association with administration of inhaled corticosteroids, however, studies with budesonide indicate that this is transient and that final adult height may ultimately be achieved (see Growth under PRECAUTIONS).
Dose-dependent HPA axis suppression has been observed with budesonide, however, this may represent a physiological adaptation rather than adrenal insufficiency (see HPA axis suppression and adrenal insufficiency under PRECAUTIONS). The lowest dose that results in clinically relevant adrenal insufficiency has not been established.
No negative effects on bone mass have been observed in adults treated with inhaled budesonide at recommended doses. In children, bone mineral density should be interpreted with caution as an increase in bone area may reflect an increase in bone volume (see Bone density under PRECAUTIONS).
Rare reports of skin bruising have occurred following treatment with inhaled glucocorticosteroids.
Psychiatric symptoms such as behavioural disturbances, nervousness, restlessness and depression have been observed with budesonide as well as other glucocorticosteroids.
Facial skin irritation has occurred in a few cases when a nebuliser with a face mask has been used. To prevent irritation, the face should be washed after each use of PULMICORT RESPULES delivered via a nebuliser with a face mask.
Rarely, PULMICORT may provoke bronchoconstriction in hyperreactive patients. Bronchospasm may be treated with an inhaled β₂-agonist.

The metabolism of budesonide is primarily mediated by CYP3A, a subfamily of cytochrome P450. Inhibitors of this enzyme e.g. ketoconazole and itraconazole, can therefore increase systemic exposure to budesonide. This is of limited clinical importance for short-term (1-2 weeks) treatment with CYP3A inhibitors, but should be taken into consideration during long-term treatment.

Instructions for Use/Handling: 1. Prepare the nebuliser for filling.
2. Detach one PULMICORT RESPULES from the rack by twisting it firmly.
3. Shake the respule.
4. Twist the top off the respule.
5. Squeeze the contents into the reservoir of the nebuliser. Do not dilute the contents unless instructed to do so by the physician. In some cases, it may be necessary to use only a part of the respule content to obtain the prescribed dose. The physician or pharmacist will advise the patient accordingly.
6. Use the nebuliser as directed, ensuring that the contents of the reservoir are completely used up.
7. After use, clean the nebuliser in accordance with the manufacturer's recommendations. Also remember to wash patient's face and rinse the mouth out with water. After each nebulisation, the mouthpiece or face mask should be rinsed in warm water and dried.
PATIENT INSTRUCTIONS: PULMICORT is not intended for rapid relief of acute episodes of asthma where an inhaled short-acting bronchodilator is required.
The patient should be instructed in the proper use of the inhaler device considered appropriate for his/her particular needs. A full set of instructions are provided with each pack of PULMICORT.
In patients in whom aerosol metered-dose inhalation technique is incorrect or unamenable to easy correction, PULMICORT TURBUHALER could be substituted.
Patients also receiving bronchodilators by inhalation should be advised to use the bronchodilator before PULMICORT in order to enhance its penetration into the bronchial tree. Several minutes should elapse between the use of the two inhalers.
IMPORTANT: PULMICORT is not intended for rapid relief of acute episodes of asthma where an inhaled short-acting bronchodilator is required.
CAUTION: The contents of PULMICORT RESPULES are for inhalation via a nebuliser, and should not be swallowed or injected.
Use only as directed by the physician.
Avoid getting the aerosol in the eyes (wear goggles as suggested).
Wash the face and rinse the mouth out with water after administration of each dose of PULMICORT.
Do not exceed the prescribed dose.
PULMICORT RESPULES can be mixed with 0.9% saline and with solutions for nebulisation of terbutaline, salbutamol, sodium cromoglycate and ipratropium. The admixture should be used within 30 minutes.
PULMICORT should be added to the nebuliser immediately before use.
Medications for nebulisation should not be mixed in advance.
Nebulisers and PULMICORT (budesonide) RESPULES: For all solutions used in a nebuliser, it is very important that the mist (aerosol) produced is the right size and strength to work correctly in the lungs.
With PULMICORT RESPULES, this can best be achieved by using a compressed air jet nebuliser which gives an output of at least 6 to 8 litres per minute.
A jet nebuliser creates the aerosol mist to be inhaled by using air pumped via an electric compressor or compressed oxygen from a tank.
Check the instruction manual or with the manufacturer of the nebuliser to ensure the nebuliser fulfills the requirements.
Take note that it is not recommended that an ultrasonic nebuliser is used with PULMICORT RESPULES.
An ultrasonic nebuliser creates a high frequency signal to produce vibrations in the liquid and to provide a fog of small droplets which can be inhaled. Use of this type of nebuliser may cause the treatment with PULMICORT RESPULES to be ineffective. Follow the other instructions in the package.

Store below 30°C. Do not refrigerate. Unused respules should be discarded three months after opening of foil packs.
PULMICORT RESPULES should be protected from light by keeping them in the foil envelope.

Antiasthmatic & COPD Preparations

R03BA02 - budesonide ; Belongs to the class of other inhalants used in the treatment of obstructive airway diseases, glucocorticoids.

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