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| 1. What doses of Pulmicort Turbuhaler are considered well tolerated? |
| Safety can be divided into local safety and systemic safety. Systemic
safety in children is also described in Paediatric
asthma
Depending on test methods used systemic activity of inhaled steroids may be detected after inhalation of various doses. Continuous systemic glucocorticoid activity may or may not translate into clinically detectable systemic side effects. Suppressive effects on the hypothalamic-pituitary-adrenal (HPA) axis measured as 24-hour excretion of urinary cortisol, integrated 24-hour plasma cortisol or ACTH tests are sensitive enough to detect systemic activity. Morning cortisol is insensitive as cortisol is secreted in a pulse-way manner. A normal HPA axis function during treatment with inhaled steroids is generally considered as a clear marker of safety. Compared with placebo no suppressive effects on the HPA-axis have been found with doses of Pulmicort Turbuhaler up to and including 800 µg daily. A daily dose of 1600 µg has in some studies resulted in a small but statistically significant suppression but not in all. The response to ACTH has usually been normal with doses including 1600 µg per day, but not 3200 µg per day. Patients treated with oral glucocorticosteroids have often low plasma cortisol values and a poor response to ACTH. Change of treatment from oral to inhaled corticosteroids usually results in an improved level of plasma cortisol and improved response to ACTH. It should be remembered that dose-response curves are individual. Single patients may be more susceptible for the effects of corticosteroids. Therefore the lowest clinically effective dose should always be identified. Current asthma treatment guidelines do not recommend daily doses of inhaled corticosteroids exceeding 1000 µg per day, as patients requiring higher doses are better treated with combinations of lower doses of inhaled corticosteroids plus e.g. long-acting inhaled ß2-agonists or theophylline. This also means in clinical practice that all doses recommended in asthma treatment guidelines are well tolerated doses for long-term use. |
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| 2. Does Pulmicort Turbuhaler cause local side-effects? |
| Treatment with inhaled corticosteroids may result in local side effects
such as candidiasis, cough and dysphonia.
The frequency of local side-effects in patients using Pulmicort pMDI (and other inhaled steroid pMDIs) has been found to be in the order of 20-25% (1). The use of a large volume spacer attached to the pMDI reduced the risk for oropharyngeal candidiasis as large corticosteroid particles deposit in the spacer instead in the pharynx and on the vocal cords. Local side-effects can generally be reduced if patients after inhalation are washing their mouth with a gulp of water. The use of large volume spacers does not reduce the frequency of coughing. However, changing treatment from Pulmicort pMDI + spacer to Pulmicort Turbuhaler significantly reduced the number of coughs within 5 minutes after inhalation (2) (see Fig.1.). Cough frequency after inhalation |
 Fig.1. The number of coughs within 5 minutes after inhalation of budesonide in a randomized, crossover study in 28 patients. From Reference 2. The frequency of local side effects was recorded in a 2-year study in 154 patients by Selroos et al. Changing treatment from pMDI + spacer to Pulmicort Turbuhaler reduced the frequency of local side-effects from 23% to 5.8 % (1) (Table 1). All the patients reporting local side-effects during treatment with Turbuhaler had had the same side-effects previously while using a pMDI with spacer. In a series of 90 patients starting treatment with Pulmicort Turbuhaler only 3 cases of sore throat occurred during a 2-year period. But not a single case of dysphopnia or oropharyngeal candidiasis (1). Local side effects |
 Table 1. Frequency of local side-effects in patients previously treated or not treated with inhaled corticosteroids. From Reference 1. A recent review found that the frequency of local side effects after inhalation of fluticasone propionate was significantly higher than that after inhalation of budesonide or BDP (3).
1. Selroos O, Backman R, Forsén K-O et al. Local side-effects during 4-year treatment with inhaled corticosteroids - a comparison between pressurized metered-dose inhalers and Turbuhaler. Allergy 1994; 49: 888-890. 2. Engel T, Heinig JH, Malling HJ et al. Clinical comparison of inhaled budesonide delivered either via pressurized metered dose inhaler or Turbuhaler. Allergy 1989; 44: 220-225. 3. Adams N, Bestall JM, Jones PW. Fluticasone versus beclomethasone or budesonide for chronic asthma. Cochrane Database Syst Rev 2002; 1: CD002310. |
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| 3. Does Pulmicort have an effect on the HPA-axis? |
| As described above (Safety
of Pulmicort Turbuhaler :1. What doses of Pulmicort are considered well
tolerated?) high doses of inhaled corticosteroids ( >1600 µg
per day of Pulmicort Turbuhaler) may suppress the HPA-axis function. However,
even after long-term treatment with high doses very few cases of adrenocortical
insufficiency have been reported.
In a 1-year study in patients using daily doses of 800 µg or 1600 µg of Pulmicort Turbuhaler no decrease in basal plasma cortisol or in ACTH-stimulated plasma cortisol was detected (1) (Fig.1.). HPA-axis during 1 year |
 Fig.1. Basal and ACTH-stimulated plasma cortisol in a 1-year study with daily doses of 800 µg and 1600 µg of Pulmicort Turbuhaler. In oral steroid dependent patients normalization of plasma cortisol
levels usually occur when treatment with budesonide Turbuhaler is started
(1) (see Fig.2) |
 Fig.2. Basal plasma cortisol values and ACTH-stimulated levels in oral steroid dependent patients having subnormal baseline values and receiving treatment with 800-1600 µg of Pulmicort Turbuhaler for 1 year. From Reference 2. Irani et al reported results of 1-year extension opel label studies in infants and young children who had participated in three 12-week double-blind studies using Pulmicort Respules (2). Their review included 447 children receiving budesonide compared with 223 children receiving conventional asthma therapy. No clinically or statistically significant differences in basal or adrenocorticotropic hormone-stimulated plasma cortisol concentrations were observed.
1. Kemp J, Pulmonary and Turbuhaler Study Group. Long-term safety and efficacy of Pulmicort (budesonide) Turbuhaler in asthma. 1995 Abstract presented at the Annual Meeting of the American Academy of Allergy and Immunology and American Thoracic Society. AAAI and ATS Conference on asthma, Theory and Treatment, Chicacgo, USA, July 15-17 1995 (Abstract book page 13). 2. Irani A-M, Cruz-Rivera M, Fitzpatrick S, et al. Effects of budesonide inhalation suspension on hypothalamic-pituitary-adrenal-axis function in infants and young children with persistent asthma. Ann Allergy Asthma Immunol 2002; 88: 306-312. |
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| 4. Does treatment with Pulmicort cause growth retardation? |
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The potential effects of inhaled corticosteroid therapy on growth in children have received widespread attention. Several short-term studies using stadiometry (accurate measurements of height) have reported reductions in growth in asthmatic children treated with inhaled corticosteroids. Similarly, short-term studies using knemometry (a sensitive measure of lower leg growth) have shown reductions in growth rate at medium doses of Pulmicort. It is now recognized, however, that these short-term studies are of limited value predicting the effects of long-term treatment with inhaled corticosteroids, for several reasons. a) growth rate in normal children is variable over short periods of
time In longer-term studies with inhaled corticosteroids the effect on growth has been most marked at the beginning of treatment (1). There is clear evidence from studies with Pulmicort that catch-up growth occurs following this initial decrease in growth rate (2,3). Because of the conflicting results between short-term and intermediate-term clinical studies it is obvious that long-term study results are required showing the final height of children treated with inhaled corticosteroids. Such results have been obtained in an continuing long-term study involving 332 children with asthma (4), of whom 300 were treated with Pulmicort at doses titrated according to disease severity. To date 142 Pulmicort-treated children have reached their adult height. The mean daily dose of Pulmicort in these children has been 412 µg and the duration of treatment has ranged from 3 to 13 years (average 9.2 years). There was no significant difference between the final height attained by these children and their predicted final height (Fig.1.) Final height |
 Fig.1. Relationship between final adult height and predicted adult height in 142 asthmatic children treated with Pulmicort for an average of 9.2 years at a mean daily dose of 412 µg (range 110-877 µg). In a cross sectional study in Sweden it was also found that adolescents with asthma treated with Pulmicort attained normal final height (5).
1. Doull IJ, Campbell MJ, Holgate ST. Duration of growth suppressive
effects of regular inhaled corticosteroids. Arch Dis Child 1998; 78:
172-173. |
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| 5. Can treatment with Pulmicort cause cataract and/or glaucoma? |
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Posterior subcapsular cataract formation and increased intraocular pressure (glaucoma) are considered adverse effects of oral corticosteroid treatment. An analysis of pooled data from four prospective studies with Pulmicort Turbuhaler showed no significant difference between patients treated with Pulmicort Turbuhaler 100-800 µg twice daily or placebo-treated patients (1). Studies in children have shown that long-term treatment with Pulmicort is not asociated with an increased risk for cataracts or raised intraocular pressure (2). Similarly, in the large HEICA study an independent panel of ophthalmologists could not detect any posterior subcapsular opacities in lens photographs from any of the children (3). A pooled analysis of data from eight studies in children treated with budesonide suspension for nebulisation, 0.25 - 2 mg per day, revealed no cases of subcapsular or lenticular cataracts (4). Post-marketing surveillance (approximately 222 million treatment-days) has shown only one case of cataracts in patients treated with budesonide Respules (4).
1. Duh MS, Walker AM, Lindmark B, Laties AM. Intraocular pressure and budesonide inhalation therapy: lack of association in a mixed asthmatic population treated with therapeutic doses for up to 20 weeks. Ann Allergy Asthma Immunol 1999; 82: 76 2. Agertoft L, Larsen FE, Pedersen S. Posterior subcapsular cataracts, bruises and hoarseness in children with asthma receiving long-term treatment with inhaled budesonide. Eur Respir J 1998; 12: 130-135. 3. Turpeinen M, Kari O, HEICA Study Group. No changes in intraocular pressure and no posterior subcapsular opacities in children treated for 18 months with budesonide Turbuhaler. Am J Respir Crit Care Med 2001; 163: A851. 4. Szefler S, Fitzpatrick S, Cruz-Rivera M, Lyzell E. Lack of cataracts and other localized adverse events in children treated with nebulized budesonide inhalation suspension. Eur Respir J 2001; 18, suppl 33: 442s. |
| 6. Is treatment with Pulmicort safe during pregnancy? |
| Severe asthma is associated with an increased risk of perinatal complications,
but with adequate treatment and asthma control the outcome of pregnancy
in asthmatic women is not significantly different from that in non-asthmatic
women. Achievement of good asthma control mostly requires treatment with
inhaled corticosteroids.
The safety of Pulmicort treatment during pregnancy has been documented in a large prospective study (1) using data from the Swedish Birth registry, which includes practically all children born in Sweden (about 100,000 per year). Since 1994 this registry has included information on drug use, which is collected prospectively during pregnancy, thus avoiding the risk of retrospective recall bias. Between 1995 and 1997, a total of 2014 infants were born to mothers who had been using Pulmicort during early pregnancy. The incidence of congenital malformations in these children was similar to that in the general population (see Fig.1.). Budesonide during pregnancy |
 Fig.1. Incidence of congenital malformations and number of orofacial clefts in children born to asthmatic women treated with budesonide during pregnancy and in the general population. No statistically significant differences were found. From Reference 1. Similar evidence for the safety of budesonide during pregnancy was reported from the Swedish Medical Products Agency showing an identical incidence of congenital malformations (3.6%) in asthmatic women treated with budesonide and in the general population (2). These data has resulted in recommendations for use of Pulmicort during pregnancy (3) and the regulatory labelling for use during pregnancy has also been changed from category C to category B by the Food and Drug Administration in the US.
1. Källén B, Rydhstroem H, Åberg A. Congenital malformations after use of inhaled budesonide in early pregnancy. Obstet Gynecol 1999; 93: 392-395. 2. Ericson A, Källén B. Use of drugs during pregnancy - unique Swedish registration method that can be improved. Inf Läkemedelsverket (Information from the Swedish Medical Products Agency) 1999; 1: 8-11. 3. American College of Obstetricians and Gynecologists and the American College of Allergy, Asthma and Immunology. The use of newer asthma and allergy medications during pregnancy. Ann Allergy Asthma Immunol 2000; 84: 475-480. |
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| 7. Does Pulmicort cause bone fractures or osteoporosis? |
| Long-term treatment with oral glucocorticosteroids is associated with
an increased risk of osteoporosis and bone fractures. There has been a
fear that also treatment with inhaled corticosteroids might have similar
effects.
Several cross-sectional studies have indicated that patients using inhaled corticosteroids have a lower bone mineral density (BMD) than asthmatic patients not using them (or than healthy control subjects). These study results are difficult to interpret as patients using inhaled corticosteroids usually have a more severe asthma than non-treated patients. Patients with severe asthma may be less mobile and physical inactivity is associated with a loss of bone mass. The effects of long-term treatment with Pulmicort Turbuhaler on the incidence on vertebral fractures and BMD was investigated in a prospective, randomized 2-year study involving 374 patients aged 18-66 years (1). Patients were randomised to receive Pulmicort Turbuhaler 400 µg per day, beclomethasone dipropionate 500 µg per day via pMDI, or non-steroid reference treatment. There were no significant differences in BMD (Fig.1.) or the incidence of fractures between the three groups. Further evidence that long-term treatment with Pulmicort has no significant effect on BMD comes from the EUROSCOP study in patients with COPD (2). All patients underwent standardised spinal radiography at the beginning and at the end of the 3-year trial. In addition BMD was measured in a subgroup of 161 patients. Neither an increased risk of fractures nor a decrease in BMD (Fig. 1.) was found. EUROSCOP: Bone mineral density |
 Fig.1. Changes in BMD measured in a) the lumbar spine (L2-L4) and b) femoral neck, during treatment with budesonide Turbuhaler 400 µg twice daily or placebo for 3 years. (From Reference 2.) Also studies with Pulmicort in children have documented unchanged BMD compared to control patients (3) or children treated with placebo or nedocromil (4). The incidence of fractures in 45 double-blind studies with Pulmicort revealed a fracture incidence of 0.9% in Pulmicort patients (n=6574) compared with 1.4% in placebo-treated patients (n=1996). It can therefore be concluded that treatment with Pulmicort at approved clinical doses seems not to be associated with an increased risk of osteoporosis or bone fractures.
1. Tattersfield AE, Town GI, Johnell O et al. Bone mineral density in subjects with mild asthma randomised to treatment with inhaled corticosteroids or non-corticosteroid treatment for two years. Thorax 2001; 56: 272-278. 2. Johnell O, Pauwels R, Löfdahl C-G, et al. Bone mineral density in patients with chronic obstructive pulmonary disease treated with budesonide Turbuhaler. Eur Respir J 2002; 19: 1058-1063. 3. Agertoft L, Pedersen S. Bone mineral density in children with asthma receiving long-term treatment with inhaled budesonide. Am J Respir Crit Care Med 1998; 157: 178-183. 4. The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000; 343: 1054-1063. |
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| 8. Does Pulmicort have an effect on skin? |
| Long-term treatment with glucocorticoid creams or ointments result in
skin atrophy. Similar skin changes have not been observed during treatment
with inhaled budesonide.
In the EUROSCOP study in patients with mild COPD (1), superficial skin
bruising occurred in 10% of the patients treated with Pulmicort Turbuhaler
Skin bruising is a marker of systemic glucocorticoid activity. The adverse event as such may be more cosmetically disturbing than serious. In the long-term Pulmicort study in children there were no significant differences between the steroid-treated children and placebo-treated children in the incidence of bruising, the area covered by bruises or the tendency to bruise (2). Neither was there a correlation between the occurrence of bruises and the duration of treatment or the cumulative dose of Pulmicort.
1. Pauwels RA, Löfdahl C-G, Laitinen LA et al. Long-term treatment with inhaled budsonide in persons with mild chronic obstructive pulmonary disease who continue smoking. N Engl J Med 1999; 340: 1948-1953. 2. Agertoft L, Larsen FE, Pedersen S. Posterior subcapsular cataracts, bruises and hoarseness in children with asthma receiving long-term treatment with inhaled budesonide. Eur Respir J 1998; 12: 130-135. |
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| 9. Is treatment with Pulmicort contraindicated in patients with concomitant infections? |
| Systemic glucocorticosteroids in high doses have well-known immunosuppressive
effects which may result in an increased susceptibility to infections.
As a result concerns have been expressed that inhaled corticosteroids
may have similar effects. However, with the exception of the known association
with oropharyngeal candidiasis no systematic study has reported an association
between inhaled corticosteroid therapy and other infections, including
severe invasive infections such as tuberculosis or invasive aspergillosis.
Few events of severe infections during treatment with Pulmicort have been reported in clinical trials or post-marketing surveillance experience. Asthma exacerbations are frequently caused by upper respiratory tract infections (URTI). In the early years when inhaled corticosteroids were introduced, treatment was often discontinued if an URTI occurred. However, current clinical experience shows that the opposite should be recommended. When an URTI starts the dose of inhaled steroids should be increased in order to avoid a severe exacerbation. There is no evidence that the infection should be prolonged or more severe when treatment with inhaled corticosteroids is continued and the dose increased. This is also the basis for the step up strategy recommended in asthma treatment guidelines, Also in association with severe infections, such as pulmonary tuberculosis, it is no contraindication to give patients inhaled corticosteroids provided sufficient anti-tuberculosis treatment is given at the same time. |
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