4.1. Therapeutic indications

Pulmicort is recommended in patients with bronchial asthma.

4.2. Posology and method of administration

Posology

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 the 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 the 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. When transferral from oral steroids to Pulmicort is started, the patient should be in a relatively stable phase. A high dose of Pulmicort 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 the oral steroid with Pulmicort. 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.

Method of administration

Pulmicort Turbohaler is for oral inhalation.

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 minimise the risk of oropharyngeal candida infection, the patient should rinse their mouth out with water after inhaling.

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 the active substance.

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-dependent patients: 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 this occurs, treatment with inhaled budesonide should be discontinued immediately, the patient assessed and 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.

Pulmicort 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 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.

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 of impaired adrenal function. These patients may exhibit signs and symptoms of adrenal insufficiency when exposed to severe stress. Additional systemic corticosteroid treatment 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 may occur with any inhaled corticosteroids, particularly at high doses prescribed for long periods. These effects are much less likely to occur with inhalation treatment than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). It is important, therefore, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.

Reduced liver function affects the elimination of corticosteroids causing lower elimination rate and higher systemic exposure. Be aware of possible systemic side effects.

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.

Co-treatment with CYP3A inhibitors, e.g. itraconazole, ketoconazole, HIV protease inhibitors and cobicistat-containing products is expected to increase the risk of systemic corticosteroid side effects. Therefore, the combination should be avoided unless the benefit outweighs this increased risk, in which case patients should be monitored for systemic corticosteroid side effects. This is of limited clinical importance for short-term (1-2 weeks) treatment with itraconazole or ketoconazole or other potent CYP3A inhibitors, but should be taken into consideration during long-term treatment. A reduction in the dose of budesonide should also be considered (see section 4.5).

Oral candidiasis may occur during the therapy with inhaled corticosteroids. This infection may require treatment with appropriate antifungal therapy and in some patients discontinuation of treatment may be necessary (see section 4.2).

Pneumonia in patients with COPD

An increase in the incidence of pneumonia, including pneumonia requiring hospitalisation, has been observed in patients with COPD receiving inhaled corticosteroids. There is some evidence of an increased risk of pneumonia with increasing steroid dose but this has not been demonstrated conclusively across all studies.

There is no conclusive clinical evidence for intra-class differences in the magnitude of the pneumonia risk among inhaled corticosteroid products.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations.

Risk factors for pneumonia in patients with COPD include current smoking, older age, low body mass index (BMI) and severe COPD.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCS) which have been reported after use of systemic and topical corticosteroids.

Paediatric populations

Influence on growth

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be re-evaluated with the aim of reducing the dose of inhaled corticosteroid, if possible, to the lowest dose at which effective control of asthma is maintained. The benefit of the corticosteroid therapy and the possible risk of growth suppression must be carefully weighed. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.

4.5. Interaction with other medicinal products and other forms of interaction

The metabolism of budesonide is primarily mediated by CYP3A4. Co-treatment with CYP3A inhibitors, e.g. itraconazole, ketoconazole, HIV protease inhibitors and cobicistat-containing products, are expected to increase the risk of systemic side effects (see section 4.4 and section 5.2).

The combination of Pulmicort with potent CYP3A inhibitors should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side effects, in which case patients should be monitored for systemic corticosteroid side effects. If Pulmicort is co-administered with anti-fungals (such as itraconazole and ketoconazole), the period between treatments should be as long as possible. A reduction of the budesonide dose could be considered.

Limited data about this interaction for high-dose inhaled budesonide indicate that marked increases in plasma levels (on average four- fold) may occur if itraconazole, 200 mg once daily, is administered concomitantly with inhaled budesonide (single dose of 1000 µg).

Raised plasma concentrations of and enhanced effects of corticosteroids have been observed in women also treated with oestrogens and contraceptive steroids, but no effect has been observed with budesonide and concomitant intake of low dose combination oral contraceptives.

Because adrenal function may be suppressed, an ACTH stimulation test for diagnosing pituitary insufficiency might show false results (low values).

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy

Most results from prospective epidemiological studies and world-wide post-marketing data have not been able to detect an increased risk for adverse effects for the foetus and newborn child from the use of inhaled budesonide during pregnancy. 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. It is important for both foetus and mother to maintain an adequate asthma treatment during pregnancy. As with other drugs administered during pregnancy, the benefit of the administration of budesonide for the mother should be weighed against the risks to 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.

Breast-feeding

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.

Maintenance treatment with inhaled budesonide (200 or 400 micrograms twice daily) in asthmatic nursing women results in negligible systemic exposure to budesonide in breast-fed infants.

In a pharmacokinetic study, the estimated daily infant dose was 0.3% of the daily maternal dose for both dose levels, and the average plasma concentration in infants was estimated to be 1/600th of the concentrations observed in maternal plasma, assuming complete infant oral bioavailability. Budesonide concentrations in infant plasma samples were all less than the limit of quantification.

Based on data from inhaled budesonide and the fact that budesonide exhibits linear PK properties within the therapeutic dosage intervals after nasal, inhaled, oral and rectal administrations, at therapeutic doses of budesonide, exposure to the breast-fed child is anticipated to be low.

4.7. Effects on ability to drive and use machines

Pulmicort Turbohaler has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Tabulated list of adverse reactions

The following definitions apply to the incidence of undesirable effects: Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data).

Table 1 Adverse Drug Reactions (ADR) by System Organ Class (SOC) and Frequency

SOC

Frequency

Adverse Drug Reaction

Infections and infestations

Common

Oropharyngeal candidiasis

Pneumonia (in COPD patients)

Immune system disorders

Rare

Immediate and delayed hypersensitivity reactions including rash, contact dermatitis, urticaria, angioedema and anaphylactic reaction

Endocrine disorders

Rare

Signs and symptoms of systemic corticosteroid effects, including adrenal suppression and growth retardation*

Psychiatric disorders

Uncommon

Anxiety

Depression

Rare

Psychomotor hyperactivity

Sleep disorders

Aggression

Behavioural changes (predominantly in children)

Nervous System Disorders

Uncommon

Tremor**

Eye disorders

Uncommon

Cataract

Vision, blurred (see also section 4.4)

Not known

Glaucoma

Respiratory, thoracic and mediastinal disorders

Common

Cough

Hoarseness

Throat irritation

Rare

Bronchospasm

Dysphonia

Hoarseness***

Skin and subcutaneous tissue disorders

Rare

Bruising

Musculoskeletal and connective tissue disorders

Uncommon

Muscle spasm

* refer to Paediatric population, below

** based on the frequency reported in clinical trials

*** rare in children

Occasionally, signs or symptoms of systemic glucocorticosteroid-side effects may occur with inhaled glucocorticosteroids, probably depending on dose, exposure time, concomitant and previous corticosteroid exposure, and individual sensitivity (see section 4.4).

Description of selected adverse reactions

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).

In placebo-controlled studies, cataract was also uncommonly reported in the placebo group.

Clinical trials with 13119 patients on inhaled budesonide and 7278 patients on placebo have been pooled. The frequency of anxiety was 0.52% on inhaled budesonide and 0.63% on placebo; that of depression was 0.67% on inhaled budesonide and 1.15% on placebo.

Paediatric population

Due to the risk of growth retardation in the paediatric population, growth should be monitored as described in section 4.4.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard

4.9. Overdose

Symptoms

Acute overdosage with Pulmicort Turbohaler, even in excessive doses, is not expected to be a clinical problem. 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.

Management

No special emergency action needs to be taken. Treatment with Pulmicort Turbohaler should be continued at the recommended dose to control the asthma.