1. Name Of The Medicinal Product
Pulmicort® Turbohaler® 400.
2. Qualitative And Quantitative Composition
Budesonide 400 micrograms/actuation.
There are no inactive ingredients.
3. Pharmaceutical Form
Breath-actuated metered dose powder inhaler.
4. Clinical Particulars
4.1 Therapeutic Indications
Pulmicort is recommended in patients with bronchial asthma.
4.2 Posology And Method Of Administration
Pulmicort Turbohaler is for oral inhalation.
When transferring patients to Turbohaler from other devices, treatment should be individualised, whether once or twice daily dosing is being used. The drug and method of delivery should be considered.
Divided doses (twice daily):
The dosage should be individualised.
The dose should always be reduced to the minimum needed to maintain good asthma control.
Adults (including elderly) and children over 12 years of age: When starting treatment, during periods of severe asthma and while reducing or discontinuing oral glucocorticosteroids, the dosage in adults should be 200 - 1600 micrograms daily, in divided doses.
In less severe cases and children over 12 years of age, 200 - 800 micrograms daily, in divided doses, may be used. During periods of severe asthma, the daily dosage can be increased to up to 1600 micrograms, in divided doses.
Children 5 - 12 years of age: 200 - 800 micrograms daily, in divided doses. During periods of severe asthma, the daily dose can be increased up to 800 micrograms.
Once daily dosage:
The dosage should be individualised.
The dose should always be reduced to the minimum needed to maintain good asthma control.
Adults (including elderly) and children over 12 years of age: 200 micrograms to 400 micrograms may be used in patients with mild to moderate asthma who have not previously received inhaled glucocorticosteroids.
Up to 800 micrograms may be used by patients with mild to moderate asthma already controlled on inhaled steroids (e.g. budesonide or beclomethasone dipropionate), administered twice daily.
Children 5 - 12 years of age: 200 micrograms to 400 micrograms may be used in children with mild to moderate asthma who have not previously received inhaled glucocorticosteroids, or who are already controlled on inhaled steroids (e.g. budesonide or beclomethasone dipropionate), administered twice daily.
The patient should be transferred to once daily dosing at the same equivalent total daily dose; the drug and method of delivery should be considered. The dose should subsequently be reduced to the minimum needed to maintain good asthma control.
Patients should be instructed to take the once daily dose in the evening. It is important that the dose is taken consistently and at a similar time each evening.
There are insufficient data to make recommendations for the transfer of patients from newer inhaled steroids to once daily Pulmicort Turbohaler.
Patients, in particular those receiving once daily treatment, should be advised that if their asthma deteriorates (e.g. increased frequency of bronchodilator use or persistent respiratory symptoms) they should double their steroid dose, by administering it twice daily, and should contact their doctor as soon as possible.
In patients where an increased therapeutic effect is desired, an increased dose of Pulmicort is recommended because of the lower risk of systemic effects as compared with a combined treatment with oral glucocorticosteroids.
Patients maintained on oral glucocorticosteroids
Pulmicort Turbohaler may permit replacement or significant reduction in dosage of oral glucocorticosteroids while maintaining asthma control. For further information on the withdrawal of oral corticosteroids, see section 4.4.
Patients should be reminded of the importance of taking prophylactic therapy regularly, even when they are asymptomatic. A short-acting inhaled bronchodilator should be made available for the relief of acute asthma symptoms.
Instructions for the correct use of Pulmicort Turbohaler
Turbohaler is inspiratory flow-driven which means that, when the patient inhales through the mouthpiece, the substance will follow the inspired air into the airways.
Note: It is important to instruct the patient:
• To carefully read the instructions for use in the patient information leaflet, which is packed with each Turbohaler
• To breathe in forcefully and deeply through the mouthpiece to ensure that an optimal dose is delivered to the lungs
• Never to breathe out through the mouthpiece
• To rinse the mouth out with water and spit it out, or to brush the teeth after inhaling the prescribed dose, to minimise the risk of oropharyngeal thrush
The patient may not taste or feel any medication when using Turbohaler due to the small amount of drug dispensed.
4.3 Contraindications
Hypersensitivity to budesonide.
4.4 Special Warnings And Precautions For Use
Special caution is necessary in patients with active or quiescent pulmonary tuberculosis, and in patients with fungal or viral infections in the airways.
Non steroid: A therapeutic effect is usually reached within 10 days. In patients with excessive mucus secretion in the bronchi, a short (about 2 weeks) additional oral corticosteroid regimen can be given initially.
Steroid-dependent patients: When transferral from oral steroids to Pulmicort Turbohaler is started, the patient should be in a relatively stable phase. A high dose of Pulmicort Turbohaler is then given in combination with the previously used oral steroid dose for about 10 days.
After that, the oral steroid dose should be gradually reduced (by for example 2.5 milligrams prednisolone or the equivalent each month) to the lowest possible level. In many cases, it is possible to completely substitute Pulmicort for the oral steroid.
During transfer from oral therapy to Pulmicort, a generally lower systemic steroid action will be experienced which may result in the appearance of allergic or arthritic symptoms such as rhinitis, eczema and muscle and joint pain. Specific treatment should be initiated for these conditions. During the withdrawal of oral steroids, patients may feel unwell in a non-specific way, even though respiratory function is maintained or improved. Patients should be encouraged to continue with Pulmicort therapy whilst withdrawing the oral steroid, unless there are clinical signs to indicate the contrary. 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.
As with other inhalation therapy, paradoxical bronchospasm may occur, with an immediate increase in wheezing after dosing. If a severe reaction occurs, treatment should be reassessed and an alternative therapy instituted if necessary.
Patients who have previously been dependent on oral steroids may, as a result of prolonged systemic steroid therapy, experience the effects of impaired adrenal function. Recovery may take a considerable amount of time after cessation of oral steroid therapy, hence oral steroid-dependent patients transferred to budesonide may remain at risk from impaired adrenal function for some considerable time. In such circumstances, HPA axis functions should be monitored regularly.
Acute exacerbations of asthma may need an increase in the dose of Pulmicort or additional treatment with a short course of oral corticosteroid and/or an antibiotic, if there is an infection. The patient should be advised to use a short-acting inhaled bronchodilator as rescue medication to relieve acute asthma symptoms.
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 or an increase in their regular therapy, e.g., higher doses of inhaled budesonide or the addition of a long-acting beta agonist, or for a course of oral glucocorticosteroid.
Prolonged treatment with high doses of inhaled corticosteroids, particularly higher than the recommended doses, may result in clinically significant adrenal suppression. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery. These patients should be instructed to carry a steroid warning card indicating their needs. Treatment with supplementary systemic steroids or Pulmicort should not be stopped abruptly.
Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma.
It is important, therefore, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.
It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be reviewed with the aim of reducing the dose of inhaled corticosteroid, if possible, to the lowest dose at which effective control of asthma is maintained. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.
Reduced liver function may affect the elimination of glucocorticosteroids. The plasma clearance following an intravenous dose of budesonide however was similar in cirrhotic patients and in healthy subjects. After oral ingestion systemic availability of budesonide was increased by compromised liver function due to decreased first pass metabolism. The clinical relevance of this to treatment with Pulmicort is unknown as no data exist for inhaled budesonide, but increases in plasma levels and hence an increased risk of systemic adverse effects could be expected.
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 causes an increase in the systemic exposure to budesonide. Concomitant treatment with ketoconazole and itraconazole or other potent CYP3A4 inhibitors should be avoided (see section 4.5 Interactions). If this is not possible, the time interval between administration of the interacting drugs should be as long as possible. A reduction in the dose of budesonide should also be considered.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
The metabolism of budesonide is primarily mediated by CYP3A4, one of the cytochrome p450 enzymes. Inhibitors of this enzyme, e.g. ketoconazole and itraconazole, can therefore increase systemic exposure to budesonide, (see Section 4.4 Special Warnings and Special Precautions for Use and Section 5.2 Pharmacokinetic Properties). Other potent inhibitors of CYP3A4 are also likely to markedly increase plasma levels of budesonide.
4.6 Pregnancy And Lactation
Data on approximately 2000 exposed pregnancies indicate no increased teratogenic risk associated with the use of inhaled budesonide. In animal studies, glucocorticosteroids have been shown to induce malformations (see Section 5.3). This is not likely to be relevant for humans given recommended doses, but therapy with inhaled budesonide should be regularly reviewed and maintained at the lowest effective dose.
The administration of budesonide during pregnancy requires that the benefits for the mother be weighed against the risk for the foetus. Inhaled glucocorticosteroids should be considered in preference to oral glucocorticosteroids because of the lower systemic effects at the doses required to achieve similar pulmonary responses.
Budesonide is excreted in breast milk. However, at therapeutic doses of Pulmicort Turbohaler no effects on the suckling child are anticipated. Pulmicort Turbohaler can be used during breast feeding.
4.7 Effects On Ability To Drive And Use Machines
Pulmicort Turbohaler does not affect the ability to drive or to use machines.
4.8 Undesirable Effects
Clinical trials, literature reports and post-marketing experience suggest that the following adverse drug reactions may occur:
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The candida infection in the oropharynx is due to drug deposition. Advising the patient to rinse the mouth out with water after each dosing will minimise the risk.
As with other inhalation therapy, paradoxical bronchospasm may occur in very rare cases (see Section 4.4).
Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. The effect is probably dependent on dose, exposure time, concomitant and previous steroid exposure, and individual sensitivity.
4.9 Overdose
The only harmful effect that follows inhalation of large amounts of the drug over a short period is suppression of hypothalamic-pituitary-adrenal (HPA) function. No special emergency action needs to be taken. Treatment with Pulmicort Turbohaler should be continued at the recommended dose to control the asthma.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Budesonide is a glucocorticosteroid which possesses a high local anti-inflammatory action, with a lower incidence and severity of adverse effects than those seen with oral corticosteroids.
Pharmacotherapeutic group: Other drugs for obstructive airway diseases, inhalants, glucocorticoids. ATC Code: RO3B A02.
Topical anti-inflammatory effect
The exact mechanism of action of glucocorticosteroids in the treatment of asthma is not fully understood. Anti-inflammatory actions, such as inhibition of inflammatory mediator release and inhibition of cytokine-mediated immune response are probably important.
A clinical study in asthmatics comparing inhaled and oral budesonide at doses calculated to achieve similar systemic bioavailability 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.
In a provocation study pre-treatment with budesonide for four weeks has shown decreased bronchial constriction in immediate as well as late asthmatic reactions.
Onset of effect
After a single dose of orally inhaled budesonide, delivered via dry powder inhaler, improvement of the lung function is achieved within a few hours. After therapeutic use of orally inhaled budesonide delivered via dry powder inhaler, improvement in lung function has been shown to occur within 2 days of initiation of treatment, although maximum benefit may not be achieved for up to 4 weeks.
Airway reactivity
Budesonide has also been shown to decrease airway reactivity to histamine and methacholine in hyper-reactive patients.
Exercise-induced asthma
Therapy with inhaled budesonide has effectively been used for prevention of exercise-induced asthma.
Growth
Limited data from long term studies suggest that most children and adolescents treated with inhaled budesonide ultimately achieve their adult target height. However, an initial small but transient reduction in growth (approximately 1 cm) has been observed. This generally occurs within the first year of treatment (see section 4.4).
HPA axis function
Studies in healthy volunteers with Pulmicort Turbohaler have shown dose-related effects on plasma and urinary cortisol. At recommended doses, Pulmicort Turbohaler, causes less effect on the adrenal function than prednisolone 10mg, as shown by ACTH tests.
5.2 Pharmacokinetic Properties
After inhalation via Turbohaler, about 25 - 30% of the metered dose is deposited in the lungs.
Of the fraction which is swallowed, approximately 90% is inactivated by first pass metabolism in the liver.
The maximal plasma concentration after inhalation of 1 milligram budesonide is about 3.5 nmol/L and is reached after about 20 minutes.
Budesonide undergoes an extensive degree (approximately 90%) of biotransformation in 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 CYP3A4, one of the cytochrome p450 enzymes.
In a study, 100 mg ketoconazole taken twice daily, increased plasma levels of concomitantly administered oral budesonide (single dose of 10 mg) on average, by 7.8-fold. Information about this interaction is lacking for inhaled budesonide, but marked increases in plasma levels could be expected.
5.3 Preclinical Safety Data
The acute toxicity of budesonide is low and of the same order of magnitude and type as that of the reference glucocorticosteroids studied (beclomethasone dipropionate, fluocinolone acetonide).
Results from subacute and chronic toxicity studies show that the systemic effects of budesonide are less severe than, or similar to, those observed after administration of the other glucocorticosteroids, e.g. decreased body-weight gain and atrophy of lymphoid tissues and adrenal cortex.
An increased incidence of brain gliomas in male rats, in a carcinogenicity study, could not be verified in a repeat study in which the incidence of gliomas did not differ between any of the groups on active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control groups.
Liver changes (primary hepatocellular neoplasms) found in male rats in the original carcinogenicity study were noted again in the repeat study with budesonide, as well as with the reference glucocorticosteroids. These effects are most probably related to a receptor effect and thus represent a class effect.
Available clinical experience shows no indication that budesonide, or other glucocorticosteroids, induce brain gliomas or primary hepatocellular neoplasms in man.
In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not appear to be relevant in humans at the recommended doses.
Animal studies have also identified an involvement of excess prenatal glucocorticosteroids, in increased risk for intrauterine growth retardation, adult cardiovascular disease and permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behaviour at exposures below the teratogenic dose range.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Pulmicort Turbohaler contains only active drug, budesonide. There are no propellants, lubricants, preservatives, carrier substances or other additives.
6.2 Incompatibilities
None known.
6.3 Shelf Life
24 months.
6.4 Special Precautions For Storage
Do not store above 30°C.
6.5 Nature And Contents Of Container
Polyethylene container consisting of a cover screwed onto a bottom plate. Inside this is the inhaler with its main parts: a mouthpiece, a dosing mechanism and a substance store.
The device also contains a desiccant.
400 micrograms/actuation, 50 actuations.
6.6 Special Precautions For Disposal And Other Handling
See section 4.2
7. Marketing Authorisation Holder
AstraZeneca UK Ltd
600 Capability Green,
Luton, LU1 3LU, UK.
8. Marketing Authorisation Number(S)
PL 17901/0164
9. Date Of First Authorisation/Renewal Of The Authorisation
18th June 2002
10. Date Of Revision Of The Text
13th August 2009
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