Budesonide/Formoterol

Budesonide and formoterol have been combined in a single dry powder device, Symbicort® Turbuhaler® (budesonide/formoterol 160/9–640/18 μg/day), in an effort to simplify asthma management. The efficacy of budesonide/formoterol as maintenance therapy in patients with asthma has been examined in several randomised studies.

Twice-daily budesonide/formoterol was significantly more effective than an equivalent or higher daily dose of budesonide alone or high-dose fluticasone propionate alone at improving peak expiratory flow (PEF) in adults with predominantly moderate persistent asthma. Symptom control and the risk of mild exacerbations were significantly improved versus budesonide alone. Moreover, budesonide/formoterol appeared to be as effective as concurrent therapy with equivalent dosages of budesonide and formoterol administered via separate inhalers in adults with moderate persistent asthma.

Budesonide/formoterol administered once daily was as effective as twice-daily administration (equivalent daily doses) and more effective than once-daily budesonide in adults with moderate persistent asthma.

Twice-daily budesonide/formoterol significantly improved PEF compared with budesonide in paediatric patients with asthma.

Adjustable maintenance dosing with budesonide/formoterol was associated with significantly less study drug use than fixed dosing with budesonide/formoterol in adults with predominantly mild or moderate persistent asthma. In two of three studies (all longer than 4 months’ duration), the risk of exacerbations was significantly lower with adjustable than with fixed dosing, but no difference was detected in four short-term studies. Symptom severity was maintained or improved in most patients receiving either treatment regimen.

In adults with moderate-to-severe persistent asthma, adjustable maintenance dosing with budesonide/formoterol reduced the rate of exacerbations and reliever medication use compared with fixed dosing with salmeterol/fluticasone propionate.

Budesonide/formoterol was well tolerated in both fixed and adjustable dosing regimens.

In conclusion, in patients with persistent asthma symptoms despite treatment with inhaled corticosteroids, budesonide/formoterol administered via a single dry powder Turbuhaler® device is an effective, well tolerated, convenient treatment option, which may have the potential for improved compliance. It appears to be as effective as treatment with budesonide and formoterol administered via separate inhalers and is more effective than budesonide monotherapy in improving PEF, controlling symptoms and preventing mild exacerbations. Adjustable maintenance dosing with budesonide/formoterol is associated with a lower overall dosage and appears to maintain control as effectively as fixed dosing.

Budesonide and formoterol target different aspects of asthma pathogenesis. Budesonide is a potent corticosteroid, whereas formoterol is a potent and selective long-acting β2-agonist, with a significantly faster onset of effect than salmeterol.

In randomised, double-blind trials (n = 286–523) in adults (three of four trials) and in paediatric patients (one trial) with asthma, mean forced expiratory volume in 1 second (FEV₁) was significantly greater after 12 weeks with twice-daily budesonide/formoterol 160/4.5–320/9μg or once-daily budesonide/formoterol 320/9μg than with inhaled corticosteroids alone. Additionally, twice-daily budesonide/formoterol 320/9μg significantly improved FEV₁ in adults with asthma compared with twice-daily salmeterol/fluticasone propionate 50/250ji.g in a randomised trial (n = 658) with a 4-week, double-blind phase and a 6-month, open-label extension phase.

Budesonide/formoterol administered via Turbuhaler® is considered to produce bioequivalent systemic exposures to those of budesonide and formoterol administered via separate inhalers. Mean budesonide lung deposition ranges from 32% to 44% of the delivered dose and the drug appears to be more centrally deposited in patients with asthma than in healthy volunteers. The systemic availability of swallowed budesonide is low because of extensive first-pass hepatic metabolism.

Maximum serum concentrations (C_max) of budesonide occur within 30 minutes after inhalation, with similar absorption characteristics seen in children and adults. Budesonide is extensively biotransformed in the liver to metabolites, which have <1 % of the activity of budesonide. Budesonide has a short (2–4 hours) elimination half-life (t1/2β).

Mean lung deposition of formoterol is 2849% of the delivered dose. The absorption of inhaled formoterol is rapid, with C_max being reached within 10 minutes of inhalation. Formoterol is mostly metabolised by the liver into predominantly inactive conjugates. The ty1/2β is 17 hours.

Budesonide and formoterol appear to have no pharmacokinetic interactions with each other when administered in combination. Potent inhibitors of the cytochrome P450 3A4 isoenzyme (e.g. ketoconazole) are considered likely to increase plasma concentrations of budesonide.

Numerous well designed, randomised studies have examined the efficacy of budesonide/formoterol in patients with persistent asthma in a variety of severity stages.

Twelve weeks’ treatment with twice-daily budesonide/formoterol 80/4.5-320/ 9μg was significantly more effective than an equivalent or higher daily dose of budesonide at improving peak expiratory flow (PEF) and symptom control and reducing the risk of mild exacerbations in clinical trials in adults (n = 362–523) with predominantly moderate persistent asthma. Additionally, twice-daily budesonide/formoterol 160/4.5μg was superior to twice-daily fluticasone propionate 250μg for most of these outcomes (n = 344).

Budesonide/formoterol (12 weeks’ therapy) appeared to be as effective as concurrent therapy with equivalent dosages of budesonide and formoterol administered via separate inhalers, and both were more effective than budesonide monotherapy in 362 adults with moderate persistent asthma.

Budesonide/formoterol administered once daily was as effective as twice-daily administration of the same daily dose in a trial in adults (n = 523) with moderate persistent asthma.

Twice-daily budesonide/formoterol 160/9μg for 12 weeks significantly improved PEF compared with an equivalent dosage of budesonide monotherapy in 286 paediatric patients with moderate persistent asthma.

In adults with predominantly mild or moderate persistent asthma (n = 127-2358), symptom severity was similarly maintained or improved in the majority of patients receiving either fixed (two inhalations twice daily) or adjustable (1–4 inhalations twice daily in response to symptoms) dosing with budesonide/formoterol even though the adjustable-dosing group generally received significantly less study drug. Significantly fewer patients who adjusted budesonide/formoterol dosage experienced >1 exacerbations in two of three studies longer than 4 months’ duration but no difference was detected in four short-term studies.

The odds of achieving a well controlled asthma week were similar with adjustable-dose budesonide/formoterol and fixed-dose salmeterol/fluticasone propionate in a study in 658 adults with moderate-to-severe persistent asthma. Adjustable dosing (1–4 inhalations twice daily) of budesonide/formoterol 160/4.5 μg/inhalation reduced the rate of exacerbations (by 40%) and reliever medication use compared with fixed-dose salmeterol/fluticasone propionate (50/250ji.g twice daily).

Budesonide/formoterol produced similar health-related quality of life (HR-QOL) improvements to treatment with equivalent dosages of the monocom-ponents administered via separate inhalers. Additionally, no between-group difference in HR-QOL was reported in the largest trial (n = 3297) that compared fixed and adjustable dosing with budesonide/formoterol.

Budesonide/formoterol appeared to be as well tolerated as budesonide plus formoterol (equivalent dosages) via separate inhalers in a 6-month, open-label, randomised study in adults with moderate persistent asthma. At least one adverse event occurred in 77% and 69% of single- and separate-inhaler recipients; the most common adverse event in both groups was respiratory infection (36% vs 31%). Pharmacologically predictable adverse events such as tachycardia, tremor, throat irritation and hoarseness/dysphonia occurred at low rates (1–6.7%) in either group. The discontinuation rate due to deterioration of asthma (<3%) and the overall withdrawal rate at 6 months (<11%) were low and similar between the regimens.

Studies comparing adjustable and fixed budesonide/formoterol dosing regimens have not reported any significant tolerability differences between the two approaches to treatment. Occasional high doses of budesonide/formoterol are generally well tolerated. No clinically important ECG changes or effects on serum potassium, pulse rate, blood pressure, heart rate, blood glucose level or plasma lactate level occurred with 10 additional doses of budesonide/formoterol 160/4.5 μg/inhalation in a randomised, crossover trial in adults with asthma.

A statistically significant incremental cost, from the perspective of a Swedish healthcare budget holder, of ≈$US99 per patient (1999 value) [$US7.50 per extra symptom-free day and $US6.20 per extra asthma-control day] occurred with 12 weeks’ treatment with budesonide/formoterol compared with budesonide mono-therapy; this was predominantly due to the extra cost of budesonide/formoterol.

In a 12-month study in Sweden, single-inhaler budesonide/formoterol significantly reduced total direct costs by 15% and total costs (direct and indirect) by 15% per patient compared with treatment with equivalent dosages of budesonide and formoterol administered via separate inhalers.

Adjustable dosing with budesonide/formoterol appears to result in total cost savings per patient, relative to fixed dosing, mainly as a result of reduced budesonide/formoterol use.