Pulmicort Respules

Budesonide.

'PULMICORT RESPULES' 0.5 mg/2 mL: Each mL contains budesonide 0.25 mg.
'PULMICORT RESPULES' 1 mg/2 mL: Each mL contains budesonide 0.5 mg.

Pharmacotherapeutic group: Other anti-asthmatics, inhalants, glucocorticoids. ATC-code: R03B A02.
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 hyperresponsiveness 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.
Pharmacodynamics: Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect.
Topical anti-inflammatory effect: The exact mechanism of action of glucocorticosteroids in the treatment of asthma is not fully understood. Anti-inflammatory actions involving T-cells, eosinophils and mast cells, such as inhibition of inflammatory mediator release and inhibition of cytokine-mediated immune response are probably important. The intrinsic potency of budesonide, measured as the affinity to the glucocorticoid receptor, is about 15 times higher than that of prednisolone.
A clinical study in asthmatics comparing inhaled and oral budesonide at similar plasma concentrations demonstrated statistically significant evidence of efficacy with inhaled but not oral budesonide compared with placebo. Thus, the therapeutic effect of conventional doses of inhaled budesonide may be largely explained by its direct action on the respiratory tract.
Budesonide has shown anti-anaphylactic and anti-inflammatory effects in provocation studies in animals and patients, manifested as decreased bronchial obstruction in the immediate as well as the late allergic reaction.
Exacerbations of asthma: Inhaled budesonide, administered once or twice daily, has been shown to effectively prevent exacerbations of asthma in both children and adults.
Exercise-induced asthma: Therapy with inhaled budesonide, administered either as once or twice daily has been effective when used for prevention of exercise-induced bronchoconstriction.
Budesonide has been shown to decrease airway reactivity to histamine and methacholine in hyperreactive patients.
Clinical exacerbations of COPD: Several studies on nebulised budesonide, 4-8 mg/day have 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 (COPD Assessment Test (CAT).
In a multi-center randomised controlled, single-blind study involving 471 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) 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.
Growth: Asthma as well as inhaled glucocorticosteroids may affect growth.
Effects of Pulmicort Nebuliser Suspension on growth have been studied in 519 children (age 8 months to 9 years) in three prospective randomised open label studies.
Overall, there was no significant difference in growth between children treated with Pulmicort Nebuliser Suspension and those treated with conventional asthma therapy. Two studies (n= 239 and 72 respectively) showed a 7 mm and 8 mm greater growth after one year's treatment with Pulmicort Nebuliser Suspension compared to the control group, conventional asthma therapy including inhaled glucocorticosteroids (not statistically significant), while in one study (n = 208) the growth during one year was 8 mm lower in the Pulmicort Nebuliser Suspension group than in the control group, conventional asthma therapy without inhaled glucocorticosteroids (statistically significant difference).
Pharmacokinetics: Absorption: In adults the systemic availability of budesonide following administration of Pulmicort Respule via a jet nebuliser is approximately 15% of the nominal dose and 40% to 70% of the dose delivered to the patients.
A minor fraction of the systemically available drug comes from swallowed drug. The maximal plasma concentration, occurring about 10 to 30 min after start of nebulisation is approximately 4 nmol/L after a single dose of 2 mg.
Distribution: Budesonide has a volume of distribution of approximately 3 L/kg. Plasma protein binding averages 85-90%.
Biotransformation: Budesonide undergoes an extensive degree (~90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone, is less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by CYP3A, a subfamily of cytochrome p450.
Elimination: The metabolites of budesonide are excreted as such or in conjugated form mainly via the kidneys. No unchanged budesonide has been detected in the urine. Budesonide has high systemic clearance (approximately 1.2 L/min) in healthy adults, and the terminal half-life of budesonide after iv dosing averages 2-3 hours.
Linearity: The kinetics of budesonide are dose-proportional at clinically relevant doses.
Children: In 4-6 years old asthmatic children, the systemic availability of budesonide following administration of Pulmicort Respule via a jet nebuliser (Pari LC Jet Plus with Pari Master compressor) is approximately 6% of the nominal dose and 26% of the dose delivered to the patients. The systemic availability in children is about half that in healthy adults. The maximal plasma concentration, occurring approximately 20 min after start of nebulisation is approximately 2.4 nmol/L in 4-6 years old asthmatic children after a 1 mg dose.
Budesonide has a systemic clearance of approximately 0.5 L/min in 4-6 years old asthmatic children. Per kg body weight children have a clearance which is approximately 50% greater than in adults. The terminal half-life of budesonide after inhalation is approximately 2.3 hours in asthmatic children. This is about the same as in healthy adults.
The exposure (Cmax and AUC) of budesonide following administration of a single 1 mg dose by nebulisation to 4-6 year old children is comparable to that in healthy adults given the same delivered dose by the same nebulizer system.
Toxicology: Preclinical safety data: Results from acute, subacute and chronic toxicity studies show that the systemic effects of budesonide, eg, decreased body-weight gain and atrophy of lymphoid tissues and adrenal cortex, are less severe or similar to those observed after administration of other glucocorticosteroids.
Budesonide, evaluated in six different test systems, did not show any mutagenic or clastogenic effects.
An increased incidence of brain gliomas in male rats in a carcinogenicity study could not be verified in two repeat studies, in which the incidence of gliomas did not differ between any of the groups with active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control groups.

PULMICORT RESPULES is indicated for patients with: Treatment of bronchial asthma.
'PULMICORT' may also be used when replacement or reduction in oral steroid therapy is desirable.
Exacerbations of chronic obstructive pulmonary disease (COPD) in person without signs of acute respiratory insufficiency.
'PULMICORT RESPULES' can be used for the treatment of acute laryngotracheo-bronchitis (croup) in infants and children.

RECOMMENDED DOSE: Dosage initially, or during periods of severe asthma, or while reducing oral corticosteroids: Adults: 1-2 mg twice daily.
Children: 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: 0.25-0.5 mg twice daily.
Dosage in exacerbations of COPD: Patients should be treated with daily doses of 4 to 8 mg of 'PULMICORT RESPULES', divided into two to four administrations, until clinical improvement is achieved, but for no longer than 10 days.
The use of nebulised budesonide has not been evaluated in clinical trials in patients with an exacerbations of COPD with respiratory failure requiring invasive mechanical ventilation or admission to intensive care unit.
Time to effect in exacerbations of COPD: Following inhaled administration of 'PULMICORT RESPULES' for the treatment of exacerbations of COPD the time to symptom improvement is comparable to administration of systemic corticosteroids.
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'.
MODE OF ADMINISTRATION: '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 is 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 'RESPULE' should be discarded.
Dose division and miscibility: Pulmicort Nebuliser Suspension can be mixed with 0.9% saline and with solutions for nebulisation of terbutaline, salbutamol, fenoterol, acetylcysteine, sodium cromoglycate or ipratropium.
The admixture should be used within 30 minutes.
Single dose units can be divided, to allow dose adjustment. The single dose unit is marked with a line (Pulmicort 0.25 mg/ml and 0.5 mg/ml only). This line indicates the 1 ml volume when the single dose unit is held up-side down. If only 1 ml is to be used, empty the contents until the surface of the liquid reaches the indicator line. Store the opened single dose unit in the envelope, protected from light. Opened single dose units should be used within 12 hours.
Please note that if only 1 ml is used the remaining volume is not sterile. (See table.)

Click on icon to see table/diagram/image

Patient Instructions: 1. It is essential that the patient be instructed that 'PULMICORT' is a preventative agent, which must be taken regularly and is not to be used as sole therapy to relieve an acute asthma attack.
2. 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'.
Improvement in asthma control following inhaled administration of Pulmicort Nebuliser Suspension can occur within 3 days of initiation of treatment, although maximum benefit may not be achieved for 2-4 weeks.
Patients - maintained on oral glucocorticosteroids: Pulmicort Nebuliser Suspension may permit replacement or significant reduction in dosage of oral glucocorticosteroids with maintained or improved asthma control.
Initially, Pulmicort Nebuliser Suspension should be used concurrently with the patient's usual maintenance dose of oral glucocorticosteroid. After approximately one week the oral dose is gradually reduced to the lowest possible level. A slow rate of withdrawal is strongly recommended. In many cases it is possible to completely substitute the oral glucocorticosteroid with Pulmicort Nebuliser Suspension.
During withdrawal, some patients may experience symptoms of systemic corticosteroid withdrawal, eg, joint and/or muscular pain, lassitude and depression, despite maintenance or even improvement in pulmonary function. Such patients should be encouraged to continue with Pulmicort Nebuliser Suspension but should be monitored for objective signs of adrenal insufficiency. If evidence of adrenal insufficiency occurs, the systemic corticosteroid doses should be increased temporarily and thereafter withdrawal should be continued more slowly. During periods of stress or during a severe asthma attack, transfer patients may require supplementary treatment with systemic corticosteroids.

OVERDOSE AND TREATMENT: Acute overdosage with Pulmicort Nebuliser Suspension, even in excessive doses, is not expected to be a clinical problem.

Hypersensitivity to budesonide or any other ingredients.

Pulmicort Nebuliser Suspension is not intended for rapid relief of acute episodes of asthma where an inhaled short-acting bronchodilator is required.
If patients find short-acting bronchodilator treatment ineffective, or they need more inhalations than usual, medical attention must be sought. In this situation consideration should be given to the need for increased anti-inflammatory therapy, eg, higher doses of inhaled budesonide or a course of oral glucocorticosteroid.
Particular care is needed in patients transferring from oral steroids, since they may remain at risk of impaired adrenal function for a considerable time. Patients who have required high dose emergency corticosteroid therapy or prolonged treatment at the highest recommended dose of inhaled corticosteroids, may also be at risk. These patients may exhibit signs and symptoms of adrenal insufficiency when exposed to severe stress. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.
Some patients feel unwell in a non-specific way during the withdrawal phase, eg, pain in muscles and joints. A general insufficient glucocorticosteroid effect should be suspected if, in rare cases, symptoms such as tiredness, headache, nausea and vomiting should occur. In these cases a temporary increase in the dose of oral glucocorticosteroids is sometimes necessary.
Replacement of systemic steroid treatment with inhaled therapy sometimes unmasks allergies, eg, rhinitis and eczema, which were previously controlled by the systemic drug. These allergies should be symptomatically controlled with an antihistamine and/or topical preparations.
Reduced liver function may affect the elimination of corticosteroids. This may be clinically relevant in patients with severely compromised liver function.
In vivo studies have shown that oral administration of ketoconazole and itraconazole (known inhibitors of CYP3A4 activity in the liver and in the intestinal mucosa, see also Interactions) may cause an increase of the systemic exposure to budesonide. This is of limited clinical importance for short-term (1 to 2 weeks) treatment, but should be taken into consideration during long-term treatment.
The long-term local and systemic effects of Pulmicort Nebuliser Suspension in man are not completely known. The dose should be titrated to the lowest effective maintenance dose once control of asthma is achieved. Physicians should closely monitor the growth of children taking corticosteroids by any route and weigh the benefit of corticosteroid therapy and asthma control against the possibility of growth suppression.
Clinical studies and meta-analyses indicate that maintenance treatment of COPD with inhaled corticosteroids may lead to an increased risk of pneumonia. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbations frequently overlap.
IMPORTANT: 'PULMICORT' (budesonide) is a preventative agent and should not be used as sole therapy in the case of an acute asthma attack. If the asthma worsens the patient should consult treatment plan or consult the physician.
Effects on ability to drive and use machines: Pulmicort Nebuliser Suspension has no effect on the ability to drive and use machines.

Use in pregnancy: Results from a large prospective epidemiological study and from world-wide post marketing experience indicate no adverse effects of inhaled budesonide during pregnancy on the health of the foetus new born child.
As with other drugs the administration of budesonide during pregnancy requires that the benefits for the mother be weighed against the risks for the foetus. Inhaled glucocorticosteroids should be considered for the treatment of asthma because of the lower systemic effects compared with oral glucocorticosteroids required to achieve similar pulmonary responses.
Use in lactation: Budesonide is excreted in breast milk. However, at therapeutic doses of Pulmicort Nebuliser Suspension no effects on the suckling child are anticipated. Pulmicort Nebuliser Suspension 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 (>1/100, <1/10): Mild irritation in the throat, Candida infection in the oropharynx, Hoarseness, Coughing.
Rare (>1/10,000, <1/1,000): Nervousness, restlessness, depression, behavioural disturbances; Immediate and delayed hypersensitivity reactions including rash, contact dermatitis, urticaria, angioedema, bronchospasm and anaphylactic reaction; Skin bruising.
In rare cases, through unknown mechanisms, drugs for inhalation may cause bronchospasm.
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.
Facial skin irritation has occurred in some cases when a nebuliser with a face mask has been used. To prevent irritation the face should be washed with water after each use of 'PULMICORT RESPULES' delivered via a nebuliser with a face mask.

Budesonide has not been observed to interact with any drug used for the treatment of asthma.
The metabolism of budesonide is primarily mediated by CYP3A4, a subfamily of cytochrome P450. Inhibitors of this enzyme e.g. ketoconazole and itraconazole, can therefore increase systemic exposure to budesonide. See Precautions.
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.
At recommended doses, cimetidine has slight but clinically insignificant effect on the pharmacokinetics of oral budesonide.

Before using 'PULMICORT RESPULES' please read this monograph and follow the instructions carefully.
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 (it is suggested that patient should use eye goggles).
Wash the face and rinse the mouth out with water after administration of each dose of 'PULMICORT'.
Do not exceed the prescribed dose.
'PULMICORT' may be nebulised in combination with Bricanyl, Ventolin, Intal, Atrovent or normal saline.
'PULMICORT' should be added to the nebuliser immediately before use.
Medications for nebulisation should not be mixed in advance.
WARNING: Unused, unopened 'RESPULES' should be discarded 3 months after opening of the foil pack.
During storage 'PULMICORT RESPULES' should be protected from light by keeping them in the foil envelope.
Instructions for the use of 'PULMICORT RESPULES': 1. Prepare the nebuliser for filling.
2. Detach one Pulmicort Respule 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 the face and rinse the mouth out with water.
After each nebulisation, the mouthpiece or facemask should be rinsed in warm water and dried.
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 for the patient to inhale by using air pumped via an electric compressor or compressed oxygen from a tank.
Please check the instruction manual, or with the manufacturer of the nebuliser to ensure the nebuliser fulfils these requirements.
Please note that it is not recommended that the 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.
Opened single-dose units should be used within 12 hours.
Sterile single-dose units in a opened envelope should be used within 3 months.
Always keep unopened units in the foil envelope in order to protect from light.
Please also follow the other instructions in this pack.
For further information, please contact the physician, pharmacist.

Stored below 30°C. Do not refrigerate. Unused 'RESPULES' should be discarded three months after opening of foil packs.

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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