Children, adolescents and adults with asthma have used Turbuhaler^® as the delivery device in a number of very large asthma studies for Pulmicort^®, Oxis^® and Symbicort^®. For example, Pulmicort^® Turbuhaler^® has been used in the START, OPTIMA and FACET studies, which together comprise over 10,000 patients; Oxis^® Turbuhaler^® has been used in around 18,000 patients in studies such as RELIEF; and Symbicort^® Turbuhaler^® has been used in 25,000 patients in the product's clinical development programme.

In addition, large clinical studies have also been conducted in patients with COPD indicating effective use of Turbuhaler^® in this patient population: e.g. over 1,200 patients were randomized to treatment with Pulmicort^® Turbuhaler^® in EUROSCOP. Two large Symbicort^® COPD studies by Szafranski et al (2003) and Calverley et al (2003) were performed over 12 months including in total 1,800 patients.

Finally, there is considerable clinical experience showing efficacy in children using Turbuhaler^®. The START study included over 3,000 patients between the ages of 5 and 18 years, all of whom used Pulmicort^® Turbuhaler^®.

References

Calverley PM, et al. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J 2003;22(6):912-9.

Szafranski W, et al. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J 2003;21(1):74-81.

Ease of use of the product; good clinical effect in situations conceived as constrained; high lung deposition of the drug following inspiration leading to improved clinical efficacy; and a low incidence of local side effects all combine to make Turbuhaler^® a very effective drug delivery device.

Turbuhaler^® is easy to use due to its simple design and breath-actuated operation. There are only a few actions for the patient to follow.
Read how to use Turbuhaler

Also compliance is high with Turbuhaler^®, which is an important factor when determining therapeutic success in any chronic disease, including asthma. In a review of studies in which compliance with inhaled steroid therapy was measured by electronic counting devices, mean compliance (defined as the ratio of doses taken to those prescribed) ranged from 63-92% (Cochrane et al, 2000). One study included in this review (Bosley et al, 1994) used Pulmicort^® Turbuhaler^®; mean compliance in this study was 86%, which compares favourably with the findings obtained in studies with other dry powder inhalers included in the review.

The same review also studied the proportion of patients using their inhalers correctly (Cochrane et al, 2000) and found 78% of Turbuhaler^® patients showing 'good' inhaler technique compared with 54% for Diskhaler™ patients.

References

Bosley CM, et al. Patient compliance with inhaled medication: does combining beta-agonists with corticosteroids improve compliance? Eur Respir J 1994;7:504-9.

Cochrane MC, et al. Inhaled corticosteroids for asthma therapy. Patient compliance, devices and inhalation technique. Chest 2000;117:542-50.

Over the years, AstraZeneca has performed many preference studies for Turbuhaler^® versus dry powder inhalers such as Rotahaler™ and Diskhaler™ (see Table). These and many studies performed by other companies in this area have taught us that there seems to be a very strong correlation between the outcome of the study and the sponsoring company (Anderson, 2005). Hence, AstraZeneca has become reluctant to perform preference studies. This can be exemplified by preference studies performed with Turbuhaler^® and Diskus™/Accuhaler™, where one series of investigations reviewed by Jarvis and Faulds (1999), came to a conclusion that was the opposite of that found in two other studies by Van Spiegel and Jenner (1997) and Van der Palen et al (1998).

Summary of patient preference studies with Turbuhaler^®

In the study by Van Spiegel and Jenner (1997), 79% of patients expressed a preference for Turbuhaler^® compared with only 19% of patients who preferred Diskus™/Accuhaler™. In this study, patients were presented with a list of characteristics of an 'ideal' inhaler and asked to rate the extent to which each factor applied to the two inhalers on a scale of 1 (does not apply at all) to 5 (applied very well). Almost all features were regarded as more applicable to Turbuhaler^® than to Diskus™/Accuhaler™ (see figure below).

References to studies included in the Table

Patients can experience acute as well as longer-term local adverse events following any inhaled therapy. These local side effects of the mouth and pharynx are mainly the result of oropharyngeal drug deposition and irritation from propellants and additives. However, because Turbuhaler^® is breath-activated, has a high lung deposition and does not contain any propellants, one study reported cough frequency within 5 minutes of drug administration to be significantly lower with Pulmicort^® Turbuhaler^® than with Pulmicort^® CFC pMDI (Engel et al, 1989). Throat irritation and hoarseness were also less common with Turbuhaler^®.

The favourable safety profile of Pulmicort^® Turbuhaler^® regarding local side effects was demonstrated in the START study where patients aged 5-66 years were treated for 3 years with Pulmicort^® Turbuhaler^® 400 µg/day (200 µg/day in children) or placebo in addition to their usual asthma medication. The safety evaluation comprised 7,221 patients. The incidence of local side effects was slightly higher in the Pulmicort^® Turbuhaler^® group than placebo (Figure) but the overall incidence was low (Sheffer et al, 2005).

Incidence of local adverse events in the START study (Sheffer et al, 2005).

Long-term local side effects have also been evaluated in a 7-month comparison between Symbicort^® Turbuhaler^® and Seretide™ Diskus™/Accuhaler™. Patients received either fixed dose (FD) salmeterol/fluticasone (50/250 mg/bid), fixed dose budesonide/formoterol (2 inhalations of 160/4.5 mg bid) or adjusted dose budesonide/formoterol (2 inhalations of 160/4.5 mg bid or 160/4.5 mg bid that could be adjusted to 4 inhalations bid for 7-14 days if an asthma worsening occured (AMD)) (Andersson et al, 2004).

Candidiasis and dysphonia were considerably lower with budesonide/formoterol than salmeterol/fluticasone (see figure), and these values were lowered further with adjustable dosing of budesonide/formoterol. The difference in incidences of both candidiasis and dysphonia between salmeterol/fluticasone (Diskus™/Accuhaler™) and budesonide/formoterol (Turbuhaler^®) is the result of reduced particle deposition in the throat with budesonide/formoterol.

Proportion of asthma patients reporting candidiasis or dysphonia during treatment with either Symbicort^® Turbuhaler^® as adjustable maintenance dosing (AMD) or fixed dosing (FD), or Seretide™ Diskus™/Accuhaler™ FD (Andersson et al, 2004).

Read more about differences in between Turbuhaler^® and Diskus™/Accuhaler™.

References

Andersson T, et al. High nonrespiratory fraction of drug delivered by Diskus compared with Turbuhaler correlates with elevated side-effect levels. Eur Respir J 2004;24(Suppl 48):584S [P3584].

Engel T, et al. Clinical comparison of inhaled budesonide delivered either via pressurized metered dose inhaler or Turbuhaler. Allergy 1989;44:220-5.

Sheffer AL, et al. Long-term safety of once-daily budesonide in mild asthma: results from the START study. Ann Allergy Asthma Immunol 2005;94:48-54.

A common misunderstanding is that the inspiratory effort and the resulting peak inspiratory flow (PIF) are reduced in situations of acute airway narrowing. It is true that patients experiencing an acute asthma attack have difficulties in breathing out, but inhalation is much less affected.

It has also been shown that asthma patients reporting to the emergency ward generate a PIF through Turbuhaler^® (PIF_Turbuhaler) in the same range as patients with stable asthma. In a study of 101 patients with acute asthma the mean PIF_Turbuhaler was 59 L/min (range 25-93 L/min) and in patients with stable asthma similar values were reported (Engel et al, 1990). The correlations between PIF_Turbuhaler and the expiratory parameters (FEV₁, PEF) were too weak to allow a prediction to be made. Although not approved for use in acute asthma, there are several double-blind, randomized, clinical studies in asthmatic adults with acute severe attacks of airway obstruction which show that the bronchodilating medication (Bricanyl^®, Oxis^® and Symbicort^®) delivered by Turbuhaler^® in an emergency room setting is clinically effective. The efficacy of terbutaline or salbutamol delivered by Turbuhaler^® (as determined by increase in FEV₁) was at least similar to that of twice the amount of the drugs delivered via CFC pMDI plus large volume spacer (Nana et al, 1998; Tønnesen et al, 1994).

Equivalent efficacy with short acting ß2-agonists delivered via CFC pMDI and formoterol delivered via Turbuhaler^® has also been shown in double-blind studies (Rubinfeld et al, 2002; Malolepszy et al, 2001; Boonsawat et al, 2003). Moreover, a similar speed of onset of effect has been reported for Symbicort^® Turbuhaler^® and salbutamol pMDI plus spacer in acute asthma (Figure) (Balanag et al, 2006).

Change in FEV₁ in patients with acute asthma (mean FEV₁ 43% predicted) following two doses (administered at - 5 and 0 minutes) of either Symbicort^® Turbuhaler^® (320/9 µg, 2 inhalations) or salbutamol pMDI spacer (100 µg x 8 inhalations); total doses 1280/36 µg and 1600 µg, respectively (Balanag et al, 2006).

Read more about Turbuhaler^® and inspiratory flow

References

Balanag VM, et al. Efficacy and safety of budesonide/formoterol compared with salbutamol in the treatment of acute asthma. Pulm Pharm Ther 2006;19(2):139-147.

Boonsawat W, et al. Formoterol (OXIS^®) Turbuhaler^® as a rescue therapy compared with salbutamol pMDI plus spacer in patients with acute severe asthma. Respir Med 2003;97:1067-74.

Engel T, et al. Peak inspiratory flow and inspiratory vital capacity of patients with asthma measured with and without a new dry powder inhaler device (Turbuhaler ). Eur Respir J 1990;3:1037-41.

Malolepszy J, et al. Safety of formoterol Turbuhaler at cumulative dose of 90 µg in patients with acute bronchial obstruction. Eur Respir J 2001;18:928-34.

Nana A, et al. ß2-agonists administered by a dry powder inhaler can be used in acute asthma. Respir Med 1998;92:167-72.

Rubinfeld AR, et al. Formoterol Turbuhaler^® as reliever medication in patients with acute asthma. Eur Respir J 2006;27(4):735-41.

Tønnesen F, et al. Bronchodilating effect of terbutaline powder in acute severe bronchial obstruction. Chest 1994;105:697-700.

The inhalation volume - not the inhalation flow rate - is the main difference between a child and an adult. Children can generate similar inhalation flow rates as adults (Agertoft and Pedersen, 1998). When using a DPI such as Turbuhaler^® the inhaled volume is of less importance as the dose leaves the inhaler with the first few hundred millilitres of inhaled air (Bisgaard, 1995). In addition, PIF_Turbuhaler can be improved by training. In a study of children aged 3, 4 and 5 years, it was found that all children aged 4 and 5 years could generate a PIF_Turbuhaler >40 L/min after a training session, whereas the 3-year-old could not (Agertoft and Pedersen, 1998). The failure of the 3-year-old ones is the result of mental rather than physical ability, and applies to all dry powder and pMDI devices.

Thus, children with stable asthma, as well as those experiencing acute exacerbations, benefit from asthma treatment delivered by Turbuhaler^® in the same way as medication given via pMDI and spacer. The approved age range for children using Turbuhaler^® differs between different Turbuhaler^® brands and countries but overall the clinical evidence shows that children 5 years and older can use Turbuhaler^® effectively. Clinical studies in children with stable asthma have shown no difference in efficacy when comparing terbutaline delivered by Turbuhaler^® with pMDI attached to a large volume spacer (Nebuhaler^®) (Ahlström et al, 1989; Hultquist et al, 1989).

Children experiencing acute attacks of asthma have also been included in clinical studies with Bricanyl^®, Oxis^®, Pulmicort^® and Symbicort^®. In one study, 30 children with asthma exacerbations were given 0.5 mg terbutaline via Turbuhaler^® or pMDI attached to a large volume spacer (Rufin et al, 1993). FEV₁ was measured after 15 min and 30 min, and no difference in FEV₁ values between treatments were noted. Similar results were seen in a separate double-blind, randomized, parallel-group study in 112 children (mean age 10.5 years; range 6-16 years) presenting with an acute asthma exacerbation (Drblik et al, 2003). Mean baseline FEV₁ was 25-60% predicted normal; terbutaline 0.5 mg/10 kg body weight was given via Turbuhaler^® (n=57) or pMDI and spacer (n=55) at time 0 and 30 min later. No difference in response between the two treatments was observed.

References

Agertoft L, Pedersen S. Importance of training for correct Turbuhaler use in preschool children. Acta Paediatr 1998;87:842-7.

Ahlström H, et al. Treatment of asthma in pre-school children with inhalation of terbutaline in Turbuhaler compared with Nebuhaler. Allergy 1989;44:515-8.

Bisgaard H. Delivery of inhaled medication to children. J Asthma 1995;34:443-67.

Drblik S, et al. Comparative efficacy of terbutaline sulphate delivered by Turbuhaler dry powder inhaler or pressurised metered dose inhaler with Nebuhaler spacer in children during an acute asthmatic episode. Arch Dis Child 2003;88:319-23.

Hultquist C, et al. A double-blind comparison between a new multi-dose powder inhaler (Turbuhaler ) and metered dose inhaler in children with asthma. Allergy 1989;44:467-70.

Rufin P, et al. Efficacy of a powder inhaler (Turbuhaler) in moderate asthmatic crises in children. Rev Mal Respir 1993;10:545-50.

Patients with COPD, whether in a stable state or experiencing an exacerbation, are able to generate a PIF_Turbuhaler sufficiently high to benefit from medications delivered via Turbuhaler^®. Large placebo-controlled studies of 6-12 month duration with Oxis^® or Symbicort^® have demonstrated the usefulness of the given treatments, e.g. Calverley et al (2003); Szafranski et al (2003).

Time to first exacerbation in patients with COPD receiving either Symbicort^®, Pulmicort^®, Oxis^® or placebo via Turbuhaler^®. Data from Calverley et al (2003).

Changes in mean forced expiratory volume in 1 second (FEV₁) compared with baseline after a 2-week optimization period with oral prednisolone and inhaled formoterol in patients with COPD randomised to 12 months' treatment with either Symbicort^®, Pulmicort^®, Oxis^® or placebo via Turbuhaler^®. (Data from Calverley et al, 2003).

Moreover, the clinical effects reported in these two studies did not differ with severity of COPD or FEV₁ <30% predicted or >30% predicted (Borgström et al, 2004).

This data has been substantiated by lung deposition measurements using Oxis^® Turbuhaler^®, which shows no influence of PIF_Turbuhaler values in these COPD patients (Derom et al, 2004).

Preliminary data also suggest that Symbicort^® Turbuhaler^® in high doses could be used in the treatment of acute COPD exacerbations, providing improvements on the same level as conventional treatment (Cassola et al, 2004).

In summary, these data show that Turbuhaler^® is very effective in patients with COPD.

References

Borgström L, et al. Lack of interaction between disease severity and therapeutic response with budesonide/formoterol in a single inhaler. Am J Respir Crit Care Med 2004;169(Suppl 7):A517.

Calverley PM, et al. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J 2003;22(6):912-9.

Cazzola M, et al. Efficacy of a combination therapy with single inhaler budesonide/formoterol in the treatment of acute exacerbations of COPD (AECOPD). Eur Respir J 2004;24(Suppl 48):252s, Abs 1659.

Derom E, et al. Lung deposition of formoterol Turbuhaler^® in patients with moderate to severe COPD. Am J Respir Crit Care Med 2004;169(7 Suppl):A611.

Szafranski W, et al. Efficacy and safety of budesonide/formoterol in a single inhaler in the management of COPD. Eur Respir J 2003;21(1):74-81.

Children, adolescents and adults with asthma have used Turbuhaler^® as the delivery device in a large number of asthma studies (some involving very large numbers of patients), in the treatment of acute asthma, and in everyday life. In addition, Turbuhaler^® is an effective delivery device for treating patients with COPD. The device is easy to use, has high lung deposition of the drug following inspiration leading to improved clinical efficacy; and has low incidence of local side effects. All combined, this makes Turbuhaler^® a very effective drug delivery device.