Bronchial asthma.

The dosage of Pulmicort Turbuhaler is individual.
Initially, at the beginning of inhaled corticosteroid therapy, for therapy during periods of severe asthma or when scaling down or withdrawing oral corticosteroids the dosage should be:

Children aged 5 – 7 years: 100-400 micrograms per day, divided into 2-4 inhalations. The full daily dose may be given in one administration.

Children aged 7 years and older: 100-800 micrograms per day, divided into 2-4 inhalations. With daily doses up to 400 micrograms the full dose may be given in one administration.

Adults: The normal dose range is 200-800 micrograms per day, divided into 2-4 inhalations. In more severe cases daily doses of up to 1600 micrograms may be needed. With daily doses up to 400 micrograms the full dose may be given in one administration.
The maintenance dose should be the lowest possible.

It is possible that the patient will not taste or perceive any medicine when Pulmicort
Turbuhaler is used; this is because such a small amount of substance is dispensed.
After a single dose an effect may be expected after a few hours. The full therapeutic effect is only achieved after several weeks of treatment. Treatment with Pulmicort Turbuhaler is a prophylactic therapy with no demonstrated effect on acute disorders.

Clinical trials indicate that a larger amount of budesonide is deposited in the lungs when administered with Pulmicort Turbuhaler, compared with Pulmicort pMDI. If a patient in a stable phase is transferred from Pulmicort pMDI to Pulmicort Turbuhaler a reduction in dose may therefore be appropriate.
In patients in whom an increased therapeutic effect is desired, on account of the lower risk of systemic side effects, in general an increase of the Pulmicort Turbuhaler dose is to be recommended in preference to combination treatment with oral corticosteroids.

Patients dependent on oral steroids:

When transfer from oral steroids to Pulmicort Turbuhaler is initiated the patient’s condition must be relatively stable. For 10 days a high dose of Pulmicort Turbuhaler is given in conjunction with the previously used dose of oral steroids. After that, the oral dose should be reduced gradually by e.g. 2.5 mg prednisolone or equivalent per month to the lowest possible level. The oral steroid can often be withdrawn completely.

There is no experience of treatment of patients with impaired hepatic or renal function. Since budesonide is predominantly eliminated through hepatic metabolism, increased exposure may be expected in patients with severe cirrhosis of the liver.

Instructions for correct use of Pulmicort Turbuhaler:
It is important that the inhaler is used correctly. A detailed description of how the Turbuhaler is used is supplied with every pack.
To minimise the risk of oropharyngeal candida infection, the patient should rinse their mouth out with water after inhaling.

Budesonide is not intended for rapid relief of acute episodes of asthma where an inhaled short-acting bronchodilator is required.

Care is needed in patients transferring from oral steroids, since they may remain at risk of impaired adrenal function for a considerable time. 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. 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.

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 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.

Regular monitoring of growth is recommended in children and adolescents receiving long- term treatment with corticosteroids, irrespective of the administration form. The benefits of corticosteroid treatment must be placed in relation to possible risks of inhibition of growth.
Reduced liver function affects the elimination of corticosteroids, causing lower elimination and higher systemic exposure. Be aware of possible systemic side effects.

Concomitant use of ketoconazole, itraconazole, HIV protease inhibitors or other potent CYP3A4 inhibitors should be avoided. If this is not possible, the period between treatments should be as long as possible (see also section 4.5).
Special caution is necessary in patients with active or quiescent pulmonary tuberculosis, and in patients with fungal or viral infections in the airways.
Oral candidiasis may occur during the therapy with inhaled corticosteroids. This infection may require treatment with appropriate antifungal treatment and in some patients discontinuation of treatment may be necessary (see also section 4.2).

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 must be instructed to contact their physician if the effect of the treatment generally diminishes, as repeated inhalations for severe asthma attacks must not delay the initiation of other important therapy. In the event of acute deterioration the treatment should be supplemented with a course of oral steroid for a short period.
During the transfer from oral steroid therapy to Pulmicort Turbuhaler the patient may experience the return of previous symptoms such as muscle and joint pain. In these cases a temporary increase of the oral steroid dose may sometimes be necessary. If, in isolated cases, fatigue, headache, nausea, vomiting or similar symptoms occur, a generally unsatisfactory effect of the steroid should be suspected.

When systemic steroid treatment is replaced by Pulmicort Turbuhaler, allergies, e.g. rhinitis and eczema, are sometimes revealed, which were previously controlled by the systemic treatment.

The metabolism of budesonide is primarily mediated by CYP3A4. Inhibitors of this enzyme, e.g. ketoconazole, itraconazole and HIV-protease inhibitors can therefore increase systemic exposure to budesonide several times (see section 4.4). Since there are no data to support a dosage recommendation, the combination should be avoided. If this is not possible, the period between treatments should be as long as possible, and a reduction of the budesonide dose could also 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 1,000 μg).

Raised plasma concentrations of and increased 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).

Pregnancy:
Results from approximately 2,000 pregnancies have not revealed any increased risk of malformations as a result of treatment with budesonide. Animal studies have shown that glucocorticosteroids can induce malformations (see 5.3), but with the recommended dosage this is judged not to be relevant for humans.

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, the aim must be the lowest effective dose of budesonide, and the risk of a worsened asthmatic state must also be taken into account.

Lactation:
Budesonide is excreted in breast milk. However, at therapeutic doses of Pulmicort Turbuhaler no effects on the suckling child are anticipated. Pulmicort Turbuhaler can be used during breast-feeding.

Pulmicort Turbuhaler has no influence on the ability to drive and use machines.

To report any side effect(s):

• Saudi Arabia:

- National Pharmacovigilance Center (NPC):
o Fax: +966-11-205-7662
o Call NPC at :
+966-11-2038222 Exts: 2317-2356-2353-2354-2334-2340
o Toll free: 8002490000
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc

• Other GCC states:

- Please contact the relevant competent authority.

Frequencies are defined as: very common (≥1/10); common (≥1/100, <1/10); uncommon
(≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000).

On account of the risk of Candida infections in the oropharynx the patient must rinse the mouth with water after every dose.

There is an increased risk of pneumonia in patients with newly diagnosed COPD starting treatment with inhaled corticosteroids. However, a weighted analysis of 8 pooled clinical trials involving 4,643 COPD patients treated with budesonide and 3,643 patients randomised to non-inhaled corticosteroid treatments sis not demonstrate an increased risk of pneumonia. The results from the first 7 of these 8 trials have been published as a meta-analysis.

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

Acute overdosage with Pulmicort Turbuhaler, even in excessive doses, is not expected to cause any clinical problems. If used chronically in high doses, systemic effects of glucocorticosteroids such as hypercortisolism and adrenal suppression can occur.

Pharmacotherapeutic group: Inhalation drugs for obstructive airway diseases.
ATC code: R03BA02

Budesonide is a glucocorticosteroid with powerful local anti-inflammatory effects.

The exact mechanism of action of glucocorticosteroids in the treatment of asthma is not fully understood. Anti-inflammatory effects such as inhibited release of inflammatory mediators and inhibition of cytokine-mediated immune response are probably important. The activity of budesonide, measured as its affinity for glucocorticosteroid receptors is approx. 15 times higher than that of prednisolone.

Budesonide has shown anti-inflammatory effects, such as reduced bronchial obstruction during both the early and the late phase of an allergic reaction. In hyper-reactive patients budesonide reduces the histamine and metacholine reactivity in the airways.

Studies have shown that the earlier budesonide treatment is initiated after the onset of asthma, the better the lung function that can be expected.

Dose-related suppression of plasma and urinary cortisol have been observed in studies in healthy volunteers treated with Pulmicort Turbuhaler. At recommended doses, Pulmicort Turbuhaler, causes a significantly lower effect on the adrenal function than prednisolone 10 mg, as shown by ACTH tests.

In children over the age of 3 years no systemic effects have been detected with doses up to 400 micrograms/day. In the dose range 400-800 micrograms/day biochemical signs of a systemic effect may occur, while such signs are common with daily doses in excess of 800 micrograms.

An initial small but generally transient reduction in growth (approximately 1 cm) has been observed, which usually occurs within the first year of treatment. Several long-term studies indicate that children and adolescents treated with inhaled budesonide on average achieve their adult target height. However, in a double-blind long-term study, in which a budesonide dose of 400 micrograms daily was administered, children and adolescents treated with inhaled budesonide became on average 1.2 cm shorter as adults than those randomised to receive placebo. See section 4.4 about titration to the lowest effective dose and about monitoring of growth in children.

Inhalation therapy with budesonide is effective in preventing effort-induced asthma.

Absorption:
Inhaled budesonide is absorbed rapidly, and peak plasma concentrations are reached within 30 minutes after inhalation. In studies, the average deposition of budesonide in the lungs after
inhalation via Turbuhaler has been shown to be 25-35 % of the given dose. The systemic bioavailability is approx. 38 %.

Distribution and metabolism:
Binding to plasma proteins is approx. 90%. The volume of distribution is approx. 3 litres/kg. Budesonide undergoes extensive (approx. 90 %) first-passage metabolism in the liver to metabolites with low glucocorticosteroid activity. The glucocorticosteroid activity for the main metabolites, 6-beta-hydroxybutesonide and 16-alpha hydroxyprednisolone, is less than
1% of that of budesonide.

Elimination:
Budesonide is eliminated through metabolism, which is catalysed principally by the enzyme CYP3A4. The metabolites are excreted in the urine in unchanged or conjugated form. Only
negligible amounts of unchanged budesonide are recovered in the urine. Budesonide has a high systemic clearance (approx. 1.2 litres/min), and the half-life in the plasma after intravenous administration is on average 4 hours. The pharmacokinetics of budesonide are proportional to the dose at relevant dosages.

The pharmacokinetics of budesonide in children and in patients with impaired renal function are not known. Exposure to budesonide may be greater in patients with hepatic disease.

In toxicity studies budesonide caused only the expected glucocorticoid effects.

Budesonide has not displayed any genotoxic effects.

In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations) in various species. However, these
animal experimental results do not seem to be relevant in humans at the recommended doses.

Pulmicort Turbuhaler contains no excipients.

Not relevant.

Do not store above 30°C. Must be stored with the protective cap in place.

Pulmicort Turbuhaler is an inspiration-driven multi-dose powder inhaler made of plastic. Each inhaler contains 200 doses.

No special requirements.