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| 1. What is the evidence that Pulmicort can be given once daily? |
A large series of controlled clinical studies have shown that patients with mild to moderate asthma can be well controlled using once-daily Pulmicort. These clinical studies are summarized in the tables below and have
been discussed in a review (1).
1. O'Byrne PM (ed). Once-daily corticosteroid therapy in asthma: Improving compliance with budesonide - A seminar-in-print. Drugs 1999;58(Suppl 4):1-53. |
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| 2. What is the explanation for the once-daily dosing of Pulmicort? |
| A prerequisite for once-daily dosing is a sufficiently long duration
of action of the active compound. Recently a new mechanism for the metabolism
and local retention of budesonide was identified that may explain the
prolonged duration of anti-inflammatory activity in the airways after
inhalation (Fig.1.). This explanation may also stay behind the clinical
experience with once-daily dosing of budesonide.
Experiments in rats showed that the retention of radiolabelled budesonide
in airway tissue was markedly longer than would be expected from the
rather low lipophilicity of the compound (1). Subsequent kinetic studies
showed that, in airway tissue, budesonide undergoes a rapid and extensive,
but reversible intracellular esterification with long-chain fatty acids
(2). Budesonide fatty acid esters have little affinity for the glucocorticoid
receptor (1), but appear to form an intracellular depot from which active
budesonide is slowly released by the action of intracellular lipases.
After inhalation or intratracheal instillation of radioactive budesonide,
about 80% of bound radioactivity is in inactive esterified form within
20 minutes (1). Similarly, in vitro studies with human bronchial
epithelial cells showed that more than 90% of the total intracellular
budesonide was found to be in esterified form after incubation with
radiolabelled budesonide for 6 hours (3). Bioavailability and functional
importance of the budesonide ester pool has also been proven in cellular
experiments where the ester formation was blocked by an acyl coenzymeA:cholesterol
acyltransferase (ACAT)-blocker. Under these conditions the cells stored
much less budesonide, and its kinetical and functional duration was
shorter (4). Importantly, formation of inactive budesonide esters has
also been demonstrated in human lung (5) and nose (6), tissues in which
they predominantly and specifically seem to occur. These studies have
also suggested that pronounced esterification in airways is unique for
budesonide among the inhaled steroids. |
 Fig. 1. Esterification of budesonide in airway cells could account for the prolonged duration of action of inhaled budesonide in the airways and for an increased benefit:risk ratio. The formation of budesonide esters increases the lung retention of budesonide to a much greater extent than its systemic retention, thus prolonging its action and increasing the benefit:risk ratio of therapy with budesonide (Fig.2.) (7). Budesonide esterification - pharmacokinetic modelling |
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1. Miller-Larsson A, Mattsson H, Hjertberg E, Dahlbäck M, Tunek
A, Brattsand R. Reversible fatty acid conjugation of budesosnide: novel
mechanism for prolonged retention of topically applied steroid in airway
tissue. Drug Metab Dispos 1998;26:623-30. |
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| 3. Can Pulmicort be given once daily as a starting dose? |
| The START (inhaled Steroid Treatment As Regular Therapy in early asthma)
study investigated whether Pulmicort once-daily could be used as a starting
dose for patients with newly detected mild asthma.
This was a randomized double-blind, placebo-controlled 3-year study in 7241 patients from 32 countries, aged 5 to 66 years, having mild persistent asthma for less than 2 years and no previous treatment with glucocorticosteroids (1). Data on 7165 patients was available for analysis. The 3-year study was completed by 5155 patients. The drop-out rate and the mean time in the study were comparable for the Pulmicort and placebo groups. The age of the patients (mean ± SD) was 24±15 years. 27% of them were 6-10 years old, 17% 11-17 years old and the rest 18 years or older. The patients had symptoms, such as wheeze, cough, dyspnoea, and chest tightness at least weekly, but not as often as daily, during 3 months prior to entering the study. All had reversible airway obstruction, defined as an increase in FEV1 of more than 12% after inhalation of terbutaline 0.5 mg via Turbuhaler, or 1.0 mg via a pMDI, or a fall in FEV1 of more than 15% on exercise testing, or a variation of more than 15% between the two highest and the two lowest PEF values over a 14-day period. Patients were not eligible for the study if they had received asthma treatment for more than 2 years, or if they had received more than 30 days of glucocorticosteroid treatment per year prior to the study. Patients were also ineligible if they had a prebronchodilator FEV1<60% and a postbronchodilator FEV1<80% predicted normal. The results of the START study showed that early treatment with Pulmicort significantly reduced the risk of having an asthma exacerbation, and improved airway function and asthma control. Once-daily budesonide can thus well be used as starting regimen in patients with mild asthma. Read more: |
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| Fig.1. Flow chart of the START study
1. Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma - the START study. Eur Respir J 2002; 20, suppl 38: 305s. |
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| 4. Is once-daily as effective as twice-daily regimen in patients with mild asthma? |
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Once-daily administration of drugs is preferred by patients compared with more frequent dosing. Once-daily regimens thus improve patients' compliance with treatment. Jónasson et al performed a double-blind, randomized study in 163 children (mean age 9.9 years, range 7-16 years) with mild asthma who were given Pulmicort Turbuhaler 100 µg or 200 µg once daily, placebo, or Pulmicort Turbuhaler 100 µg b.i.d. for 12 weeks (1). The primary variable of efficacy was the change in morning PEF. No statistically significant differences were seen between the four treatments. For FEV1 and PC20 methacholine, a significant difference was seen between the 100 µg Pulmicort twice-daily dose and placebo, but not between placebo and the once-daily doses. After 12 weeks all three Pulmicort treatments protected statistically significantly better than placebo against the decrease in FEV1 after exercise (see Fig. 1.). Once daily in children - exercise induced asthma |
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| Fig. 1. Changes in maximum fall in FEV1 after exercise in
children treated with once-daily or twice-daily budesonide. Both treatment
regimens were effective (significantly different from placebo) but without
a difference between the treatments.
Mintz et al (2) included 288 adult patients with mild to moderate asthma using inhaled BDP 200-250 µg twice daily into a placebo-controlled, double-blind, 12-week study. The patients were randomized to treatment with Pulmicort Turbuhaler 200 µg once daily in the evening, 100 µg twice daily or placebo in a 2:2:1 ratio. After 12 weeks, morning PEF had increased statistically significantly vs placebo in both Pulmicort groups and without a statistically significant difference between them (see Fig. 2). Asthma symptoms and bronchodilator use were significantly reduced in both groups receiving active treatment. There were no statistically significant differences in any measured outcome variable between the once-daily and twice-daily Pulmicort groups. Once daily vs twice daily |
 Fig. 2. Changes in morning PEF in patients with mild-to-moderate asthma treated with BDP 200-250 µg twice daily and randomized to once- or twice daily treatment of a daily dose of 200 µg of budesonide. No difference in efficacy was seen between the two dosing regimens in this placebo-controlled study.
1. Jónasson G, Carlsen K-H, Blomqvist P. Clinical efficacy of low-dose inhaled budesonide once or twice daily in children with mild asthma not previously treated with steroids. Eur Respir J 1998;12:1099-1104. 2. Mintz S, Alexander M, Li JHS, Mayer PV. Once-daily administration of budesonide Turbuhaler was as effective as twice-daily treatment in patients with mild to moderate persistent asthma. J Asthma 2002; 39: 203-210. |
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| 5. What type of asthma patients can start with once-daily Pulmicort from the beginning? |
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A large series of controlled clinical studies have shown that patients
with mild or moderate persistent asthma can start treatment with once
daily Pulmicort Turbuhaler(1). The daily dose should usually be 200
µg or 400 µg once daily in adults and 100 µg or 200
µg in children with asthma. The START study in patients with newly
diagnosed mild asthma (asthma for less than two years) is a good example
of this treatment regimen (2). The inclusion criteria of the START study
are shown below:
Studies with 400 µg once daily in children and 800 µg once daily in adult patients have also been performed with good results. However, patients with severe persistent asthma and some patients with moderate persistent asthma can be better controlled on treatment with divided doses.
1. O'Byrne PM (ed). Once-daily corticosteroid therapy in asthma: Improving compliance with budesonide - A seminar-in-print. Drugs 1999;58(Suppl 4):1-53. 2. Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma - the START study. Eur Respir J 2002; 20, suppl 38: 305s. Read more: |
| 6. Which doses of Pulmicort can be given once daily? |
| Controlled clinical studies have shown that Pulmicort Turbuhaler 200
µg, 400 µg and 800 µg once daily can be used in adult
patients with mild or moderate persistent asthma. Children with mild or
moderate persistent asthma have been well controlled with the doses 100
µg, 200 µg and 400 µg once daily. These doses have been
found effective as initial doses as well as maintenance doses after tapering
from higher doses.
Patients with more severe asthma requiring higher maintenance doses of Pulmicort should have divided doses. The studies showing the efficacy of the above mentioned doses have been discussed in a review paper (1).
Read more. |
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| 7. When can a twice-daily dose be adjusted to an once-daily regimen? |
| Asthma treatment and management guidelines recommend a step down and
step up strategy for inhaled corticosteroids (1).
Patients with moderate or severe asthma may have started treatment with e.g. 400 µg to 800 µg twice daily of Pulmicort. The total daily dose of Pulmicort can be reduced when a normal airway function (>80% predicted normal), normal night time sleep, normal exercise tolerance, and a limited requirement for "as needed" ß2-agonists have been achieved, indicating a limited and infrequent occurrence of asthma symptoms. There is some evidence that adding the degree of non-specific bronchial hyperresponsiveness (histamine or methacholine challenge tests) to the criteria for dose adjustment will further improve the degree of asthma control (2). When the total daily dose has been reduced to 400 µg in adult patients and 200 µg in children these doses can be administered once daily - in the morning or in the evening. Some patients can be well controlled also on higher once-daily doses: 800 µg once daily in adults and 400 µg once daily in children with asthma (3).
1. Global Initiative for Asthma. Global strategy for asthma management and prevention. NHLBI/WHO workshop report (based on a March 1995 meeting). NIH Publication number 95-3659, 1995. 2. Sont JK, Willems LN, Bel EH, et al. Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. Am J Respir Crit Care Med 1999;159(4):1043-1051. 3. O'Byrne PM (ed). Once-daily corticosteroid therapy in asthma: Improving compliance with budesonide - A seminar-in-print. Drugs 1999;58(Suppl 4):1-53. |
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| 8. Should a once-daily dose be tapered? |
| Patients well controlled in their asthma should have a trial with a
lower maintenance dose in order to find the minimum effective dose for
good asthma control (1).
If a patient is using once-daily doses higher than 100 µg of Pulmicort the dose can be reduced. Usually halving of the daily dose is recommended. This can be done as the dose-response curve for inhaled corticosteroids is rather flat and a difference in doses of four times is required in order to see statistically significant differences between doses. This means that a patient well controlled in her/his asthma on budesonide 800 µg once daily can reduce the dose to 400 µg once daily, and later on to 200 µg once daily and 100 µg once daily if asthma control is still good. Patients well controlled on 100 µg once daily may try to use Pulmicort only intermittently.
1. Global Initiative for Asthma. Global strategy for asthma management and prevention. NHLBI/WHO workshop report (based on a March 1995 meeting). NIH Publication number 95-3659, 1995. |
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| 9. Can once-daily Pulmicort be dosed equally well in the morning as in the evening? |
| Lung function shows a diurnal variation with the lowest values in the
early morning hours. Once-daily treatment with medications affecting airway
tonus has therefore greater possibilities to improve early morning lung
function if dosed late in the evening.
The hypothalamic-pituitary-adrenal (HPA-axis) function also has a diurnal variation with the lowest plasma cortisol values in the early morning. Glucocorticosteroids have therefore usually been given in the morning during the rising phase of plasma cortisol in order to avoid adrenal suppression. It is therefore important to document any possible differences between morning and evening dosing of once-daily medications. Jones et al performed a double-blind, randomized study in 340 patients with predominantly mild asthma (1). After a 1-week run-in period the patients were randomized to one of four treatment options: Pulmicort Turbuhaler 400 µg once daily in the morning, 400 µg once daily in the evening, 200 µg twice daily or placebo. Change in morning PEF was the primary variable of efficacy and this change was statistically significantly different for the three Pulmicort treatment groups compared with placebo (Fig.1.). No significant differences were found between the Pulmicort groups. Similarly, asthma symptom scores and use of ß2-agonists were reduced in all budesonide groups, but due to low initial values the differences vs placebo did not reach a statistically significant level. This study showed that once-daily administration of Pulmicort was equally effective when given in the morning as in the evening. Once daily - morning or evening? |
 Fig.1. Mean increase in PEF after dosing of budesonide 200 µg twice daily, 400 µg once daily in the morning and in the evening. All three dosing regimens were equally effective.
1. Jones AH, Langdon CG, Lee PS, et al. Pulmicort Turbohaler once daily as initial prophylactic therapy for asthma. Resp Med 1994;88:293-9. |
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| 10. Is once-daily dosing as safe as the same daily dose in divided doses? |
| McFadden et al performed a double-blind, randomized, parallel group,
18-week study in 309 patients who were using a maximum daily dose of 500
µg BDP and with a FEV1 of >80% predicted normal (n=133),
or who were not on inhaled corticosteroids and had a FEV1 of
60-90% predicted normal (1). The patients could therefore be classified
as having mild or moderate persistent asthma. All patients were required
to have a >15% reversibility with an inhaled ß2-agonist.
The patients were randomized to treatment with Pulmicort Turbuhaler 200 µg once daily, 400 µg once daily (reduced to 200 µg once daily after 6 weeks), or placebo. Both Pulmicort groups showed superior and statistically significant differences vs placebo regarding lung function (PEF, FEV1), asthma symptoms (morning), use of ß2-agonists and quality-of-life measurements. No significant differences were observed between the two Pulmicort groups (see Fig. 1.) Once daily maintenance treatment |
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| Fig.1. Changes in FEV1 over six plus 12 weeks in a placebo-controlled
study with once-daily budesonide treatments.
Safety was assessed by reporting adverse events, vital signs, physical examinations and laboratory tests. The incidence of most adverse events was similar in the three treatment groups. Bronchospasm was reported in 11% of placebo patients compared with 4% and 5% of the patients in the 200 µg and 400/200 µg Pulmicort groups, respectively. There were no indications of treatment-related effects on vital signs, physical examination, or any laboratory variables for haematology, clinical chemistry, and urinalysis. The effect of once daily Pulmicort on the HPA-axis has been evaluated
in three clinical studies in healthy subjects (2,3) and in patients
with asthma (4). Thorsson and Källen (3) performed a double-blind, randomized, placebo-controlled, crossover study in 24 healthy subjects. They received 800 µg Pulmicort Turbuhaler once daily in the morning, the same dose but in the evening or 400 µg twice daily. Each treatment was given for one week, with 2-week washouts in between. Blood samples were drawn for measurement of plasma cortisol before the evening dose on day 6 of each treatment period and every 2 hours during the following 22 hours. All three Pulmicort treatments produced small but statistically significant reductions in plasma cortisol (mean, 16-19%) compared with placebo (AUC0-22h). There were no significant differences between the treatments. It was concluded that Pulmicort Turbuhaler, 800 µg daily, was unlikely to produce clinically important adrenal suppression when given in one or two daily doses. No statistically significant difference was observed between morning and evening dosing. Wilson et al (4) compared the suppression of 400 and 800 µg Pulmicort with 375 and 750 µg fluticasone propionate (FP) administered via their respective pMDIs in the morning for 4 days to 10 adults with asthma. Plasma cortisol levels at 8.00 hours in the morning and overnight excretion of cortisol were measured. Compared with placebo, only the 750-µg FP dose caused a statistically significant reduction in morning cortisol levels (mean, 20%). The difference in reduction between 750 µg FP and 800 µg Pulmicort was statistically significant, but not the difference between 375 µg FP and 400 µg Pulmicort. Similarly, for the urinary excretion of cortisol, a statistically significant difference was found between the two high-dose preparations with FP treatment resulting in lower values. The effects of budesonide nebulising suspension (Pulmicort Respules)
on the HPA axis in children receiving 0.25-1.0 mg once daily have also
been studied. No evidence of HPA axis suppression was found, either
in short-term placebo-controlled studies over 12 weeks or in a 52-week
open trial (5). References: 1. McFadden ER, Casale TB, Edwards TB, et al. Administration of budesonide
once daily by means of Turbuhaler to subjects with stable asthma. J
Allergy Clin Immunol 1999;104:46-52. |
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| 11. Does once-daily Pulmicort improve compliance? |
| Treatment compliance in asthmatic patients is known to be poor. Whether
compliance is measured by patient reports or by inhalers with electronic
monitors, the results indicate that about 50-75% of patients fail to comply
with instructions. There are obviously several types of non-compliance:
patients may under-use or over-use the prescribed medication, or even
both. These behaviours also occur for different reasons and with different
outcomes. Although poor treatment outcomes are often associated with poor
compliance, it does not necessarily follow that poor compliance always
leads to poor outcome. Patients base their treatment on their perceptions
of efficacy and beliefs, and those beliefs may or may not lead to poor
compliance.
The effect of once-daily treatment on compliance is as varied as the types and causes of non-compliance (1). Once-daily treatment is likely to have an impact on only some kinds of non-compliance. For example, if a patient is taking half the dose because she or he finds it difficult to pay for the inhaler, then the introduction of once-daily treatment will have no effect if the cost to the patient remains the same. However, two types of non-compliance are particularly relevant to once-daily treatment: a) intentional under-dosage because of a dislike of medication in general, and b) forgetting to take the dose on occasion. Therefore, for many patients with well-controlled asthma, a documented, effective, once-daily treatment regimen improves compliance (2). Pulmicort can be dosed once daily as initial treatment as well as maintenance treatment after stepping down from twice-daily treatment. Compliance has not been investigated in formal clinical studies. There is, however, reason to believe that once-daily Pulmicort has improved treatment compliance.
1. Hyland ME. Rationale for once-daily therapy in asthma. Compliance
issues. Drugs 1999; 58 (suppl 4): 1-6. |
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| 12. Do patients prefer once-daily treatment? |
| Venables et al performed an open, randomized, crossover
study in 230 patients with mild asthma (1). Patients were required to
be corticosteroid-naïve or using a maximum dose of 200 µg daily,
to have a PEF >60% predicted normal, and to demonstrate a >15% reversibility
with an inhaled ß2-agonist. After a 1-week run-in period,
patients were randomized to treatment for 4 weeks with Pulmicort Turbuhaler
400 µg once daily in the evening, 200 µg twice daily or FP
200 µg twice daily via Diskhaler. The budesonide-treated patients
were then switched to fluticasone propionate (FP), and the fluticasone-treated
patients to Pulmicort. Mean morning PEF, the primary variable of efficacy,
statistically significantly improved in all three treatment groups: Pulmicort
Turbuhaler 400 µg once daily, 32 ± 6 L/min; Pulmicort Turbuhaler
200 µg twice daily, 21 ± 5 L/min; and FP 200 µg twice
daily, 33 ± 5 L/min. No statistically significant differences were
observed between the groups. The crossover design allowed patients preferences
for once- or twice-daily treatment to be assessed. Of the 104 patients who completed a preference questionnaire, 61% expressed a preference for once-daily treatment compared with 12% who preferred twice-daily treatment. This difference was statistically significant. Once-daily preference |
 Fig. 1. Patient preference during treatment with budesonide 400 µg once daily, 200 µg twice daily and FP 200 µg twice daily.
1. Venables TL, Addlestone MB, Smithers AJ, et al. A comparison of the efficacy and patient acceptability of once daily budesonide via Turbohaler and twice daily fluticasone propionate via disc-inhaler at an equal daily dose of 400 µg in adult asthmatics. Br J Clin Res 1996;7:15-32. |
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| 13. Is once-daily Pulmicort cost-effective? |
| Based on the clinical results in the study by Venables
et al (1) a cost-effectiveness analysis was also performed(2).
The total drug costs were higher with FP than with Pulmicort regimen, and this was reflected in lower cost per symptom-free day with Pulmicort (see Fig.1.). Cost-effectiveness vs FP Diskhaler® |
 Fig.1. Total drug costs per day and per symptom-free day during treatment with budesonide 400 µg once daily, 200 µg twice daily and FP 200 µg twice daily.
1. Venables TL, Addlestone MB, Smithers AJ, et al. A comparison of the efficacy and patient acceptability of once daily budesonide via Turbohaler and twice daily fluticasone propionate via disc-inhaler at an equal daily dose of 400 µg in adult asthmatics. Br J Clin Res 1996;7:15-32. 2. Venables TL, McConchie S, Fellows RM. A comparison of the cost-effectiveness of budesonide and fluticasone dry-powder devices in the management of adult asthma. Br J Med Economics 1996; 10: 315-23. |
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