1. Name Of The Medicinal Product
Easyhaler Budesonide 200 micrograms/dose inhalation powder.
2. Qualitative And Quantitative Composition
One metered dose contains 200 micrograms of budesonide.
With the Easyhaler device the delivered dose (ex-actuator) contains the same quantity of active substance as the metered dose (ex-reservoir).
Excipient: Lactose monohydrate.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Inhalation powder.
White or almost white powder.
4. Clinical Particulars
4.1 Therapeutic Indications
Treatment of mild, moderate, and severe persistent asthma.
(Note: Easyhaler Budesonide is not suitable for the treatment of acute asthma attacks.)
4.2 Posology And Method Of Administration
Method of administration: For inhalation use. For optimum response, Easyhaler Budesonide inhalation powder should be used regularly.
The therapeutic effect begins after a few days´ treatment and reaches its maximum after some weeks of treatment.
When transferring a patient to Easyhaler Budesonide from other inhalation devices, the treatment should be individualised. The previous active substance, dose regimen, and method of delivery should be considered.
The patients should be prescribed a starting dose of inhaled budesonide which is appropriate for the severity or level of control of their disease. The dose should be adjusted until control is achieved and then titrated to the lowest dose at which effective control of asthma is maintained.
Lower strengths of Easyhaler Budesonide are available for appropriate dose adjustment, if necessary.
The starting dose for adults (including the elderly and children/adolescents over 12 years of age) with mild asthma (Step 2) and for children 6 to 12 years of age is 200-400 micrograms/day. If needed, the dose can be increased up to 800 micrograms/day. For adult patients with moderate (Step 3) and severe (Step 4) asthma the starting dose can be up to 1600 micrograms/day. The maintenance dose should be adjusted to meet the requirements of an individual patient taking into account the severity of the disease and the clinical response of the patient.
Twice daily dosing
Adults with mild, moderate or severe asthma (including the elderly and children/adolescents over 12 years of age): The usual maintenance dose is 100-400 micrograms twice daily. During periods of severe asthma, the daily dose may be increased up to 1600 micrograms administered in divided (two) doses and subsequently reduced when asthma has stabilised.
Children 6 to 12 years: The usual maintenance dose is 100-200 micrograms twice daily. If needed, the daily dose may be increased up to 800 micrograms administered in divided (two) doses and subsequently reduced when asthma has stabilised.
Once daily dosing
Adults with mild to moderate asthma (including the elderly and children/adolescents over 12 years of age): In patients who have not previously received inhaled corticosteroids the usual maintenance dose is 200-400 micrograms once daily. In patients already controlled on inhaled corticosteroids (eg budesonide or beclometasone dipropionate) administered twice daily, once daily dosing up to 800 micrograms may be used.
Children 6 to 12 with mild to moderate asthma: In steroid naive patients or patients controlled on inhaled corticosteroids (eg budesonide or beclometasone dipropionate) administered twice daily the usual maintenance dose is 200-400 micrograms once daily.
The patient should be transferred to once daily dosing at the same equivalent total daily dose (with consideration of the drug and the method of delivery). The dose should be subsequently 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 the same time each evening.
There are insufficient data to make recommendations for the transfer of patients from newer inhaled corticosteroids to once daily Easyhaler Budesonide.
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 corticosteroid dose by administering twice daily. They should be advised to contact their doctor as soon as possible.
A rapid-acting inhaled bronchodilator should be available for the relief of acute symptoms of asthma at all times.
Instructions for use and handling
It should be ensured that the patient is instructed in the use of the inhaler by a doctor or pharmacist.
Easyhaler is an inspiratory flow-driven device. This 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 together with each inhaler.
- That it is recommended to keep the device in the protective cover after opening the laminate pouch to enhance the stability of the product during use and makes the inhaler more tamper proof.
- To shake and actuate the device prior to each inhalation.
- In the sitting or standing position, 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 as this will result in a reduction in the delivered dose. Should this happen the patient is instructed to tap the mouthpiece onto a table top or the palm of a hand to empty the powder, and then to repeat the dosing procedure.
- Never to actuate the device more than once without inhalation of the powder. Should this happen the patient is instructed to tap the mouthpiece onto a table top or the palm of a hand to empty the powder, and then to repeat the dosing procedure.
- To always replace the dust cap and close the protective cover after use to prevent accidental actuation of the device (which could result in either overdosing or under dosing the patient when subsequently used).
- To rinse the mouth out with water or brush the teeth after inhaling the prescribed dose to minimise the risk of oropharyngeal candidiasis and hoarseness.
- To clean the mouthpiece with a dry cloth at regular intervals. Water should never be used for cleaning because the powder is sensitive to moisture.
- To replace Easyhaler Budesonide when the counter reaches zero even though powder can still be observed within the device.
4.3 Contraindications
Hypersensitivity to budesonide or milk proteins (the excipient lactose contains milk proteins).
4.4 Special Warnings And Precautions For Use
Easyhaler Budesonide is not indicated for the treatment of acute dyspnoea or status asthmaticus. These conditions should be treated in the normal way.
Patients should be aware that Easyhaler Budesonide inhalation powder is prophylactic therapy and therefore has to be used regularly even when asymptomatic for optimum benefit and should not be stopped abruptly.
The transfer of patients treated with oral corticosteroids to the inhaled corticosteroid and their subsequent management requires special care. The patients should be in a reasonably stable state before initiating a high dose of inhaled corticosteroid through twice daily dosing in addition to their usual maintenance dose of systemic corticosteroid. After about 10 days, withdrawal of the systemic corticosteroid is started by reducing the daily dose gradually (by for example 2.5 milligrams prednisolone or the equivalent each month) to the lowest possible level. It may be possible to completely replace the oral corticosteroid with inhaled corticosteroid.Transferred patients whose adrenocortical function is impaired may need supplementary systemic corticosteroid during periods of stress e.g. surgery, infection or worsening asthma attacks. This applies also to patients who have received prolonged treatment with high doses of inhaled corticosteroids. They may also have impaired adrenocortical function which may result in clinically significant adrenal suppression and may need systemic corticosteroid cover during periods of stress.
During transfer from oral therapy to inhaled budesonide symptoms may appear that had previously been suppressed by systemic treatment with glucocorticosteroids, for example symptoms of allergic rhinitis, eczema, muscle and joint pain. Specific treatment should be co-administered to treat these conditions.
Some patients may feel unwell in a non-specific way during the withdrawal of systemic corticosteroids despite maintenance or even improvement in respiratory function. Such patients should be encouraged to continue treatment with inhaled budesonide and withdrawal of oral corticosteroid unless there are clinical signs to indicate the contrary, for example signs which might indicate adrenal insufficiency.
As with other inhalation therapies paradoxical bronchospasm may occur, manifest by an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting inhaled bronchodilator and should be treated straightaway. Budesonide should be discontinued immediately, the patient should be assessed and, if necessary, alternative treatment instituted.
When despite a well monitored treatment, an acute episode of dyspnoea occurs, a rapid-acting inhaled bronchodilator should be used and medical reassessment should be considered. If despite maximum doses of inhaled corticosteroids asthma symptoms are not adequately controlled, patients may require short-term treatment with systemic corticosteroids. In such a case, it is necessary to maintain the inhaled corticosteroid therapy in association with treatment by the systemic route.
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.
Patients who have previously been dependent on oral corticosteroids may, as a result of prolonged systemic corticosteroid therapy, experience effects of impaired adrenal function. Recovery may take a considerable amount of time after cessation of oral corticosteroid therapy and hence oral steroid-dependent patients transferred to budesonide may remain at risk from impaired adrenocortical function for some considerable time. In such circumstances hypothalamic pituitary adrenocortical (HPA) axis function should be monitored regularly.
To reduce the risk of oral candidiasis and hoarseness patients should be advised to rinse out the mouth properly or brush the teeth after each administration of inhaled corticosteroid. Oral candidiasis can be rapidly controlled by local antimycotic treatment, without the need to discontinue the treatment with inhaled budesonide.
Exacerbation of clinical symptoms of asthma may be due to acute respiratory tract bacterial infections and treatment with appropriate antibiotics may be required. Such patients may need to increase the dose of inhaled budesonide and a short course of oral corticosteroids may be required. A rapid-acting inhaled bronchodilator should be used as “rescue” medication to relieve acute asthma symptoms.
Special care and adequate specific therapeutic control of patients with active and quiescent pulmonary tuberculosis is necessary before commencing treatment with Easyhaler Budesonide. Similarly patients with fungal, viral or other infections of the airways require close observation and special care and should use Easyhaler Budesonide only if they are also receiving adequate treatment for such infections.
In patients with excessive mucous secretion in the respiratory tract, short-term therapy with oral corticosteroids may be necessary.
In patients with severe hepatic dysfunction, treatment with inhaled budesonide can result in a reduced elimination rate and hence enhanced systemic availability. Possible systemic effects may then result and therefore HPA axis function in these patients should be monitored at regular intervals.
Concomitant treatment with ketoconazole or other potent CYP3A4 inhibitors should be avoided (see Section 4.5 Interaction with other medicinal products and other forms of interaction). If this is not possible the time interval between administration of the interacting drugs should be as long as possible.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
The metabolic conversion of budesonide is impeded by substances metabolised by CYP3A4 (e.g. itraconazole, ketoconazole, ritonavir, nelfinavir, ciclosporin, ethinylestradiol and troleandomycin). The concomitant administration of these inhibitors of CYP3A4 may increase plasma levels of budesonide. This is of little clinical significance for a short term treatment (1−2 weeks), but should be taken into account for long term treatment.
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 Preclinical safety data). This is not likely to be relevant for humans given recommended doses.
Animal studies have also identified an involvement of excess prenatal glucocorticoids in increased risks 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.
During pregnancy, inhaled budesonide should only be used when the benefits outweigh the potential risks. The lowest effective dose of budesonide needed to maintain adequate asthma control should be used.
It is not known whether budesonide passes into human breast milk. Administration of inhaled budesonide to women who are breast-feeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.
4.7 Effects On Ability To Drive And Use Machines
No effects on ability to drive and use machines have been observed.
4.8 Undesirable Effects
The possible adverse reactions are presented in system organ class order sorted by frequency.
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Treatment with inhaled budesonide may result in candida infection in the oropharynx. Experience has shown that candida infection occurs less often when inhalation is performed before meals and/or when the mouth is rinsed after inhalation. In most cases this condition responds to topical anti-fungal therapy without discontinuing treatment with inhaled budesonide.
Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These may include adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma, and susceptibility to infections. The ability to adapt to stress may be impaired. The systemic effects described, however, are much less likely to occur with inhaled budesonide than with oral corticosteroids.
Lactose, the excipient in the product, contains small amounts of milk proteins and can therefore cause allergic reactions.
4.9 Overdose
Symptoms of overdose
The acute toxicity of budesonide is low. Chronic use in excessive doses can result in systemic glucocorticosteroid effects, such as increased susceptibility to infection, hypercorticism and adrenal suppression. Atrophy of the adrenal cortex can occur and the ability to adapt to stress can be impaired.
Therapeutic management of overdose
For acute overdosage, no special emergency action needs to be taken. The treatment with inhaled budesonide should be continued at the recommended dose to control asthma. HPA axis function recovers in a few days.
In stress situations, it may be necessary to administer corticosteroids as a precaution (eg high doses of hydrocortisone). Patients with adrenocortical atrophy are regarded as being steroid-dependent and must be adjusted to the adequate maintenance therapy of a systemic corticosteroid until the condition has stabilised.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Glucocorticoids. ATC code: R03BA02.
Budesonide is a glucocorticosteroid which possesses a high local anti-inflammatory action.
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.
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
A study in healthy volunteers with Easyhaler Budesonide has shown dose-related effects on plasma and urinary cortisol. At recommended doses, budesonide causes less effect on the adrenal function than prednisolone 10mg, as shown by ACTH tests.
5.2 Pharmacokinetic Properties
The activity of Easyhaler Budesoonide is due to the parent active substance, budesonide, which is provided as a mixture of two epimers (22R and 22S). In glucocorticoid receptor affinity studies, the 22R form is twice as active as the 22S epimer. These two forms of budesonide do not interconvert. The terminal half-life is the same for both epimers (2-3 hours). In asthmatic patients, approximately 15-25% of the inhaled budesonide dose from Easyhaler reaches the lungs. The largest fraction of the inhaled dose is retained in the oropharynx and swallowed if the mouth is not rinsed out.
Absorption:
After oral administration of budesonide, peak plasma concentration is achieved in about 1-2 hours and the absolute systemic availability is 6-13%. In plasma, 85-95% of budesonide is bound to proteins. In contrast, peak plasma concentration is reached approximately 30 minutes after inhalation. Most of budesonide delivered to the lungs is systemically absorbed.
Metabolism:
Budesonide is mainly eliminated by metabolism. Budesonide is rapidly and extensively metabolised in liver via cytochrome P4503A4 to two major metabolites. The in vitro glucocorticoid activity of these metabolites is less than 1% of that of the parent compound. Negligible metabolic inactivation has been observed in human lung and serum preparations.
Excretion:
Budesonide is excreted in urine and faeces in the form of conjugated and non-conjugated metabolites.
Special patient populations
The exposure to budesonide may be increased in patients with liver disease. In children the elimination half-life from plasma is markedly lower than in adults.
5.3 Preclinical Safety Data
Preclinical data with budesonide reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, or carcinogenic potential.
In animal studies on reproductive toxicity, glucocorticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal results do not seem to be relevant for humans given recommended doses.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Lactose monohydrate (which contains small amounts of milk proteins).
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
Shelf life of the medicinal product as packaged for sale: 3 years.
Shelf life after first opening the laminate pouch: 6 months.
6.4 Special Precautions For Storage
As packaged for sale
Store in the original package.
In use
Do not store above 30°C and store protected from moisture.
6.5 Nature And Contents Of Container
The multidose powder inhaler consists of seven plastic parts and a stainless steel spring. The plastic materials of the inhaler are: overcap - polyester; bulk chamber cover -LDPE; bulk chamber -polycarbonate; metering cylinder and counter wheel -acetal; mouthpiece - styrene butadiene; dust cap-polypropylene. The plastic materials of the protective cover are polypropylene and thermoplastic elastomer. The inhaler is sealed in a laminate pouch (PET, Al and PE) and packed with or without a protective cover in a cardboard box.
Packages:
Easyhaler Budesonide 200 micrograms/dose inhalation powder:
• 200 doses + protective cover
• 200 doses
• 2 x 200 doses
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
7. Marketing Authorisation Holder
Orion Corporation
Orionintie 1
FI-02200 Espoo
Finland
8. Marketing Authorisation Number(S)
PL27925/0009
9. Date Of First Authorisation/Renewal Of The Authorisation
29/11/2007
10. Date Of Revision Of The Text
04/2009
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