Pulmicort^® LS Inhaler, 50 micrograms per actuation, pressurised inhalation suspension.

Pulmicort LS Inhaler contains budesonide, 50 micrograms per actuation (puff).

For excipients see 6.1.

Pulmicort LS Inhaler is a pressurised inhalation suspension. The suspension is delivered via a pressurised metered dose inhaler (pMDI).

Pulmicort LS inhaler may also be administered via the Nebuhaler^®.

Pulmicort LS Inhaler is recommended in patients with bronchial asthma.

Adults: 200 micrograms twice daily, in the morning and in the evening. During periods of severe asthma, the daily dosage can be increased up to 1600 micrograms.

In patients whose asthma is well controlled, the daily dose may be reduced below 400 micrograms, but should not go below 200 micrograms.

The dose should be reduced to the minimum needed to maintain good asthma control.

Children: 50 to 400 micrograms to be given twice daily. During periods of severe asthma, the daily dose can be increased up to 800 micrograms.

The dose should be reduced to the minimum needed to maintain good asthma control.

Elderly: Dosage as for adults.

Patients maintained on oral glucocorticosteroids

Pulmicort Inhaler may permit replacement or significant reduction in the dosage of oral glucocorticosteroids while maintaining asthma control. For further information on the withdrawal of oral corticosteroids, see section 4.4

Instructions for the correct use of Pulmicort LS Inhaler:

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 inhaler.

• To shake the inhaler thoroughly before each actuation, in order to mix the contents of the inhaler properly.

• To breathe in slowly and deeply through the mouthpiece and to release the dose whilst continuing to breathe in.

On actuation of Pulmicort LS Inhaler, a suspension of the substance is pumped out of the canister at a high velocity. When the patient inhales through the mouthpiece at the same time as releasing a dose, the substance will follow the inspired air into the airways.

History of hypersensitivity to budesonide or any of the excipients. No other specific contraindications are known, but special care is needed in patients with lung tuberculosis, fungal and viral infections in the airways.

Patients not dependent on steroids: Treatment with the recommended doses of Pulmicort LS Inhaler usually gives a therapeutic benefit within 7 days. However, certain patients may have an excessive collection of mucous secretion in the bronchi, which reduces penetration of the active substance into the airways. In these cases, a short course of oral corticosteroids (usually 1 to 2 weeks) should be given in addition to the aerosol. After the course of the oral drug, the inhaler alone should be sufficient therapy. Exacerbations of asthma caused by bacterial infections are usually controlled by appropriate antibiotic treatment and possibly increasing the Pulmicort LS Inhaler dosage or, if necessary, by giving systemic steroids.

Steroid-dependent patients: Transfer of patients dependent upon oral steroids to treatment with Pulmicort LS Inhaler demands special care, mainly due to the slow restitution of the disturbed hypothalamic-pituitary function, caused by extended treatment with oral corticosteroids. When the Pulmicort LS Inhaler treatment is initiated, the patient should be in a relatively stable phase. Pulmicort LS Inhaler is then given in combination with the previously used oral steroid dose, for about 10 days.

After this period of time, the reduction of the oral corticosteroid dose can be started, with a dose reduction corresponding to about 1 mg prednisolone per day, every week. The oral dose is thus reduced to the lowest level which, in combination with Pulmicort LS Inhaler, gives a stable respiratory capacity.

In many cases, it may eventually be possible to completely substitute the oral steroid with Pulmicort LS Inhaler, but other cases may have to be maintained on a low steroid dosage.

Some patients may experience unease during the withdrawal period due to a decreased steroid effect. The physician may have to explain the reason for the Pulmicort LS Inhaler treatment in order to encourage the patient to continue. The length of time needed for the body to regain its natural production of corticosteroid in sufficient amounts is often extensive. 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.

During transfer from oral therapy to Pulmicort LS Inhaler, 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. 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.

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.

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 regulartherapy, e.g., higher doses of inhaled budesonide, the addition of a long-acting beta agonist or a course of oral glucocorticosteroid.

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.

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.

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. There is no information regarding the passage of budesonide into breast milk.

Pulmicort LS Inhaler does not affect ability to drive or use machines.

Clinical trials, literature reports and post-marketing experience suggest that the following adverse drug reactions may occur:

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. The incidence should be less with the Nebuhaler^®, as this reduces oral deposition.

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.

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 LS Inhaler should be continued at the recommended dose to control the asthma.

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 inhaled budesonide (administered as a dry powder via 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.

Budesonide is a glucocorticosteroid with high local anti-inflammatory effect.

Budesonide undergoes extensive 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.

About 10% of the dose is deposited in the lungs. Of the fraction of budesonide which is swallowed, approximately 90% is inactivated at first passage through the liver. The maximal plasma concentration after inhalation of 1 mg budesonide is about 2.1 nmol/L and is reached after about 10 minutes.

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.

Sorbitan trioleate, trichlorofluoromethane, dichlorotetrafluoroethane, dichlorodifluoromethane.

None known.

24 months

Do not store above 30˚C.

Do not puncture or expose the canister to high temperatures (40ºC) or direct sunlight, even when empty.

Aluminium canister containing 200 metered doses of budesonide, fitted with a valve to deliver 50 micrograms budesonide per actuation. The canister fits into a plastic adaptor made of polypropylene, with a removable cover made of polypropylene or polyethylene.

See Section 4.2 Posology and Method of Administration.

AstraZeneca UK Ltd.,

600 Capability Green,

Luton, LU1 3LU, UK.

PL 17901/0159

28^th June 2002

4th April 2004