Budelin^® Novolizer^® 200 micrograms per actuation inhalation powder

One metered dose contains 200 micrograms of budesonide.

For excipients, see 6.1

Inhalation powder

White powder

Treatment of persistent asthma

For inhalation use

Steroid naive patients and patients previously controlled on inhaled steroids:

The dose should be adapted to the requirements of each individual, the severity of the disease and the clinical response of the patient. The dose should be adjusted until control is achieved and then should be titrated to the lowest dose at which effective control of asthma is maintained

If a patient is switched from another inhalation system to Budelin Novolizer 200 micrograms the dose should be re-adjusted on an individual basis. The drug, dose regimen and method of delivery should be considered.

Posology limits:

Adults (including the elderly) and children/adolescents over 12 years of age: 200 - 1600 micrograms daily

Children 6 - 12 years: 200 - 800 micrograms daily

Twice daily dosing in adults, including the elderly should be used when starting treatment, during periods of severe asthma and while reducing or discontinuing oral glucocorticosteroids.

Once daily dosing up to 800 micrograms may be used in adults, including the elderly with mild to moderate asthma and already controlled on inhaled glucocorticosteroids (either budesonide or beclometasone dipropionate) administered twice daily.

If a patient is transferred from twice daily dosing to once daily dosing this should be at the same equivalent total daily dose (with consideration of the drug and the method of delivery) and this dose should then be reduced to the minimum dose needed to maintain effective control of asthma. The once daily regimen can be considered only when asthma symptoms are controlled.

In case of once daily dosing this dose should be taken in the evening.

In case of deterioration of asthma control (recognised by e.g. persistent respiratory symptoms, increased use of an inhaled bronchodilator) the dose of inhaled steroids should be increased. Those patients receiving the once daily dose regimen, should be advised to double their dose of inhaled corticosteroid, such that a once daily dose would be administered twice daily. In any case of deterioration of asthma control the patient should seek advice from a medical doctor as soon as possible.

A short acting inhaled β-2-agonist should be available for the relief of acute symptoms of asthma at all times.

Mode and duration of treatment:

Budelin Novolizer 200 micrograms is intended for long-term therapy and as such also for prophylactic therapy. It should be administered regularly according to the recommended schedule even when asymptomatic.

The improvement in the control of asthma can appear in 24 hours, although 1 - 2 weeks additional treatment period may be necessary to reach a maximum benefit.

In order to ensure that the active substance optimally reaches the intended site of action it is necessary to inhale steadily and as vigorously, deeply and rapidly as possible (up to the maximum inhalation depth). Budelin Novolizer 200 micrograms indicates that inhalation has been performed correctly by a clearly audible click and a colour change in the control window from green to red.

This multiple feedback mechanism of Budelin Novolizer 200 micrograms indicates that inhalation has been performed correctly. If the Budelin Novolizer 200 micrograms does not indicate that inhalation has been performed correctly, inhalation should be repeated. The inhaler remains blocked until inhalation is performed correctly.

To reduce the risk of oral candidiasis and hoarseness it is recommended that inhalation be performed before meals and that the mouth is rinsed with water or the teeth brushed after each inhalation.

Usage and handling of the Novolizer Device

Refilling

1. Lightly press together the ribbed surfaces on both sides of the lid, move the lid forwards and lift off.

2. Remove the protective aluminium foil from the cartridge box and take out the new cartridge.

3. Insert the cartridge into the Novolizer with the dosage counter facing the mouthpiece.

4. Replace the lid into the side guides from above and push down flat towards the button until it snaps into place. The cartridge can be left in the Novolizer until it has been used up, or for up to 6 months after insertion.

Note: Budelin Novolizer 200 micrograms cartridges may only be used in the Novolizer powder inhaler

Usage

1. When using the Novolizer always keep it horizontal. First remove the protective cap.

2. Completely depress the coloured button. A loud double click will be heard and the colour of the control window (lower) will change from red to green. Then release the coloured button. The colour green in the window indicates that the Novolizer is ready for use.

3. Exhale (but not into the powder inhaler).

4. Put the lips around the mouthpiece. Inhale the powder with a deep breath. During this breath a loud click should be heard, indicating correct inhalation. Hold the breath for a few seconds and then continue with normal breathing.

Note: If the patient needs to take more than 1 actuation at a time, steps 2 - 4 should be repeated.

5. Replace the protective cap on the mouth piece - the dosing procedure is now complete.

6. The number in the top window indicates the number of inhalations left.

Note: The coloured button should only be pressed immediately before inhalation.

A double inhalation in error is not possible with the Novolizer. The click sound and the change of colour in the control window indicate that inhalation has been performed correctly. If the colour of the control window does not change then inhalation should be repeated. If inhalation is not completed correctly after several attempts, then the patient should consult the doctor/physician.

Cleaning

The Novolizer should be cleaned at regular intervals, but at least every time the cartridge is changed. Instructions on how to clean the device can be found in the operating instructions attached.

Note: In order to ensure correct use of the inhaler, patients should receive thorough instructions on how to use the device. Children should only use this product under the supervision of an adult.

Budelin Novolizer 200 micrograms is contraindicated in patients with hypersensitivity to budesonide or lactose.

Budelin Novolizer 200 micrograms is not indicated for treatment of acute dyspnoea or status asthmaticus. These conditions should be treated in the normal way.

Treatment of acute exacerbations of asthma and asthma symptoms may need an increase in the dose of Budelin Novolizer 200 micrograms. The patient should be advised to use a short-acting inhaled bronchodilator as rescue medication to relieve acute asthma symptoms.

Close observation and special care is needed in patients with both active and quiescent pulmonary tuberculosis. Patients with active pulmonary tuberculosis may use Budelin Novolizer 200 micrograms only if they are treated simultaneously with effective tuberculostatics. Similarly patients with fungal, viral or other infections of the airways require close observation and special care and should use Budelin Novolizer 200 micrograms only if they are also receiving adequate treatment for such infections.

Patients who repeatedly fail to perform the inhalation correctly should consult their doctor.

In patients with severe hepatic dysfunction treatment with Budelin Novolizer 200 micrograms - similar to treatment with other glucocorticosteroids - may lead to a reduced elimination rate and an increase in systemic availability. Attention is to be paid to possible systemic effects. Therefore the hypothalamic pituitary adrenocortical (HPA) axis function of these patients should be checked at regular intervals.

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.

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.

Precautions for patients not previously treated with corticosteroids:

When Budelin Novolizer 200 micrograms is used regularly as directed, patients who have previously never or only occasionally received brief treatment with corticosteroids, should experience an improvement in breathing after approximately 1 - 2 weeks. However, extreme mucous congestion and inflammatory processes may obstruct the bronchial passages to such an extent that budesonide cannot fully exert its local effects. In such cases, inhaled therapy with Budelin Novolizer 200 micrograms should be supplemented with a short course of systemic corticosteroids (starting with 40 - 60 mg of prednisolone equivalent daily). Inhalation doses are continued after gradually reducing the dose of systemic corticosteroids.

Precautions for switching patients from systemically active corticosteroids to inhalation treatment:

Patients receiving systemic treatment with corticosteroids should be switched to Budelin Novolizer 200 micrograms at a time when their symptoms are under control. In these patients, whose adrenocortical function is usually impaired, systemic treatment with corticosteroids must not be stopped abruptly. At the beginning of the switchover, a high dose of Budelin Novolizer 200 micrograms should be given in addition to the systemic corticosteroids for about 7 to 10 days. Then, depending on the patient's response and depending on the original dose of the systemic steroid, the daily dose of the systemic corticosteroid can be reduced gradually (e.g. 1 milligram prednisolone or the equivalent each week or 2.5 milligram prednisolone or the equivalent each month). The oral steroid should be reduced to the lowest possible level and it may be possible to completely replace the oral steroid with inhaled budesonide.

Within the first few months of switching patients from systemic administration of corticosteroids to inhalation treatment, it may be necessary to resume systemic administration of corticosteroids during periods of stress or in the case of emergencies (e.g. severe infections, injuries, surgery). This applies also to patients who have received prolonged treatment with high doses of inhaled corticosteroids. They may also have impaired adrenocortical function and may need systemic corticosteroid cover during periods of stress.

Recovery from impaired adrenal function may take some considerable time. Hypothalamic pituitary adrenocortical axis function should be monitored regularly.

The patient might feel generally unwell in a non specific way during the withdrawal of systemic corticosteroids despite maintenance or even improvement in respiratory function. The patient should be encouraged to continue with inhaled budesonide and withdrawal of oral steroids unless there are clinical signs which might indicate adrenal insufficiency.

After the patient has been switched to inhalation treatment, symptoms may become manifest that had been suppressed by the previous systemic treatment with glucocorticosteroids, e.g. allergic rhinitis, allergic eczema, muscle and joint pain. Suitable drugs should be co-administered to treat these symptoms.

Inhaled budesonide should not be stopped abruptly.

Exacerbation of clinical symptoms due to acute respiratory tract infections:

If clinical symptoms become exacerbated by acute respiratory tract infections, treatment with appropriate antibiotics should be considered. The dose of Budelin Novolizer 200 micrograms can be adjusted as required and, in certain situations, systemic treatment with glucocorticosteroids may be indicated.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorbtion should not take this medicine.

Ketoconazole 200 mg once daily increased plasma levels of concomitantly administered oral budesonide (single dose of 3 mg) on average six-fold. When ketoconazole was administered 12 hours after budesonide the concentration was on average increased three-fold. Information about this interaction is lacking for inhaled budesonide, but marked increases in plasma levels could be expected. Since data to give dosage recommendations are lacking, the combination should be avoided. If this is not possible the time interval between administration of ketoconazole and budesonide should be as long as possible. A reduction in the dose of budesonide should also be considered. Other potent inhibitors of CYP3A4 (e.g. ritonavir) are also likely to markedly increase plasma levels of budesonide.

The need for use during pregnancy has to be considered with special care. Although there is no indication according to the experience in pregnant women up to now, that the teratogenic effects of budesonide, which did occur in animal experiments (see 5.3), are of any relevance in humans, other types of adverse effects (e.g. intrauterine growth retardation, atrophy of the adrenal cortex, cardiovascular disease in adulthood) which have been shown in animal studies cannot be ruled out. There is suspicion, that especially synthetic glucocorticosteroids, which can only be inactivated insufficiently by the placenta, may contribute to cardiovascular diseases in later age by an in utero programming of the fetus.

Budelin Novolizer 200 micrograms should only be used when the expected benefit outweighs 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. However, even though the systemic exposure to budesonide after inhalation therapy is low, administration of Budelin Novolizer 200 micrograms to women who are breastfeeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.

Budelin Novolizer 200 micrograms has no effect on the ability to drive or use machines.

The table below presents possible adverse drug reactions in system organ class order and sorted by frequency.

Mild mucosal irritations accompanied by difficulty in swallowing, hoarseness and cough may commonly occur .

Treatment with inhaled budesonide may result in candida infections 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.

As with other inhalation therapies, in rare cases paradoxical bronchospasm may occur, manifest by an immediate increase in wheezing after dosing. Paradoxical bronchospasm responds to a fast acting inhaled bronchodilator and should be treated straightaway. Budesonide should be discontinued immediately, the patient should be assessed and, if necessary, alternative treatment instituted.

In rare cases hypersensitivity with skin reactions such as urticaria, rash, dermatitis, pruritus and erythema were observed. There have been rare reports of angioneurotic oedema (oedema of the face, lips, eyes and throat) following inhaled budesonide. In rare cases skin bruising may occur.

In very rare cases restlessness, abnormal behaviour and increased motor activity may result.

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. In long-term treatment growth in children should be monitored regularly.

The susceptibility to infection can be increased. The ability to adapt to stress can be impaired.

Symptoms of overdose

An acute overdose of Budelin Novolizer 200 micrograms requiring counter-measures is virtually impossible. In the longer term, atrophy of the adrenal cortex can occur. The effects which are usual for glucocorticosteroids, e.g. increased susceptibility to infection, can occur. The ability to adapt to stress can be impaired.

Therapeutic management of overdose

In general, no special emergency treatment is required for acute overdosage. When inhalation treatment is continued at the prescribed dosage, the function of the hypothalamic pituitary adrenocortical axis should normalise within about 1 - 2 days.

In stress situations, it may be necessary to administer corticosteroids as a precaution (e.g. 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 steroid until the condition has stabilised.

Topically applied glucocorticoid

ATC-Code: R03BA02

Budesonide is a synthetic glucocorticoid. After oral inhalation, it has a local anti-inflammatory effect on the bronchial mucosa.

Budesonide penetrates cellular membranes and binds to a cytoplasmic receptor protein. This complex enters the nucleus and induces there the biosynthesis of specific proteins, like macrocortin (lipocortin). The hormone-like effects occur after a certain latency period (30-60 min) and result in an inhibition of phospholipase A2. It is also possible that therapeutically effective doses of budesonide (like other anti-inflammatory glucocorticosteroids) suppress cytokine-induced COX-2 expression.

Clinically, the anti-inflammatory effect results, e.g. in improvement of the symptoms, such as dyspnoea. The hyperresponsiveness of the bronchial tract to exogenic challenges is reduced.

Peak plasma levels appear approximately 30 minutes after inhalation.

Systemic bioavailability after inhalation is 73% and the concentration in human plasma after inhalation of a single dose of 1600 micrograms is 0.63 nmol/L. Plasma protein binding is 85- 90% and the volume of distribution around 3 l/kg. The elimination half-life from plasma is approximately 2.8 h in adults and markedly lower in children (1.5 h).

The trigger threshold of the Novolizer which must be overcome for successful inhalation is to be found at inspiratory flows through the inhaler of at least 35 - 50 l/min. The respirable fraction measured in vitro in the clinically relevant range is approximately 25 – 50 %. In healthy subjects, approximately 20 – 30 % of the administered dose of budesonide passes into the lungs, based on the declared dose. The remainder deposits in mouth, nose and throat and a large part of it is swallowed. The swallowed portion is subject to a high first-pass effect in the liver. Budesonide is essentially metabolised in the liver via oxidation, catalysed mainlyby the enzyme CYP3A4.

The main metabolites are 6β-hydroxybudesonide and 16α-hydroxyprednisolone which show much less pharmacological activity. This limits systemic bioavailability and toxicity.

Preclinical data revealed no special hazard for humans at therapeutic doses based on studies of chronic toxicity, genotoxicity and carcinogenicity.

Glucocorticosteroids, including budesonide, have produced teratogenic effects in animals, including cleft palate and skeletal abnormalities. Similar effects are considered unlikely to occur in humans at therapeutic doses.

Lactose monohydrate

Not applicable

• Budelin Novolizer 200 micrograms per actuation inhalation powder

Shelf life before opening the package

3 years

Shelf life after first opening the container

6 months

• Novolizer device

Shelf life before first use

3 years

In-use shelf life

1 year

To note: The functioning of the Novolizer has been demonstrated in tests for 2000 metered doses. Therefore a maximum of 10 cartridges containing 200 metered doses or 20 cartridges containing 100 metered doses can be used with this device (within a single year) prior to replacement.

Budelin Novolizer 200 micrograms should not be used after the expiry date.

Store in the original package.

When in use, Budelin Novolizer 200 micrograms should be stored protected from moisture.

Original sales packs:

1 cartridge 100 metered doses (polystyrene / polypropylene) packed in a polypropylene tube sealed by aluminium foil and 1 powder inhaler (mouthpiece in polycarbonate and device in acrylnitrilbutadienestyrol copolymer, polyoxymethylene).

1 cartridge 200 metered doses (polystyrene / polypropylene) packed in a polypropylene tube sealed by aluminium foil and 1 powder inhaler (mouthpiece in polycarbonate and device in acrylnitrilbutadienestyrol copolymer, polyoxymethylene).

2 cartridges 200 metered doses each (polystyrene / polypropylene) packed in a polypropylene tube sealed by aluminium foil and 1 powder inhaler (mouthpiece in polycarbonate and device in acrylnitrilbutadienestyrol copolymer, polyoxymethylene).

Refill packs:

1 cartridge 100 metered doses (polystyrene / polypropylene) packed in a polypropylene tube sealed by aluminium foil

1 cartridge 200 metered doses (polystyrene / polypropylene) packed in a polypropylene tube sealed by aluminium foil

2 cartridges 200 metered doses (polystyrene / polypropylene) packed in a polypropylene tube sealed by aluminium foil

Hospital pack:

1 cartridge 100 metered doses (polystyrene / polypropylene) packed in a polypropylene tube sealed by aluminium foil and 1 powder inhaler (mouthpiece in polycarbonate and device in acrylnitrilbutadienestyrol copolymer, polyoxymethylene).

Pack of 10

Samples:

1 cartridge 100 metered doses (polystyrene / polypropylene) packed in a polypropylene tube sealed by aluminium foil and 1 powder inhaler (mouthpiece in polycarbonate and device in acrylnitrilbutadienestyrol copolymer, polyoxymethylene).

1 cartridge 200 metered doses (polystyrene / polypropylene) packed in a polypropylene tube sealed by aluminium foil and 1 powder inhaler (mouthpiece in polycarbonate and device in acrylnitrilbutadienestyrol copolymer, polyoxymethylene).

“Not all pack sizes may be marketed”

Please see 4.2.

Meda Pharmaceuticals Ltd

249 West George Street

Glasgow

G2 4RB

Trading as:

Meda Pharmaceuticals Ltd

Skyway House

Parsonage Road

Takeley

Bishop's Stortford

CM22 6PU

UK

PL 15142/0054

1^st November 2009

1^st November 2009