GlaxoSmithKline Presents Asthma Data That Shows No Additional Clinical Efficacy Benefits For ICS-Treatments With A Small Particle Size

GSK presents asthma data that shows no additional clinical efficacy benefits for ICS-treatments with a small particle size

GSK today presented data at the British Thoracic Society (BTS) meeting from a systematic analysis of 25 randomised control studies (RCTs), including a meta-analysis of three key efficacy outcomes, which explored the potential impact of the particle size of different ICS-containing asthma medicines, including Seretide/Advair (salmeterol/fluticasone proprionate) on patient outcomes.

Previous studies have shown that the optimal particle size for an inhaled respiratory medicine is between 1-5 microns. However it has been suggested for both asthma and COPD that inhaled corticosteroid (ICS) containing medicines with ‘smaller’ particles (<2 microns) may deliver a more uniform distribution of the ICS within the airways, particularly in the small airways, which could translate to more favourable patient outcomes. No large-scale RCTs or analyses have been conducted to-date to investigate if particle size influences asthma or COPD patient outcomes. As a result, an extensive scientific literature review and systematic analysis was conducted to explore this hypothesis further in asthma.

This review examined the efficacy and safety outcomes from asthma studies of medicines containing fluticasone propionate (FP), which has a ‘standard’ particle size, and alternative smaller particle ICS containing medicines, HFA beclomethasone dipropionate (BDP) and ciclesonide (CIC). Adolescents/adults and paediatric data were analysed separately.

The results showed that medicines with a small particle size did not confer additional clinical efficacy or additional safety benefits in asthma patients compared to those with a ‘standard’ particle size.

Neil Barnes, Global Franchise Medical Head, Respiratory, GSK said: “Inhaled corticosteroids are the backbone of treatment for patients with persistent asthma, so the more we understand about these medicines and their relative benefits, the greater our ability to improve patient outcomes.

“These data support the positive impact that treatment with the available ICS-treatments can have, but importantly what they also show is that although individual molecules have different characteristics, a small particle size does not offer any additional benefit for the majority of patients and should not drive treatment choice. As clinicians it is important when making treatment decisions for our patients that we focus on the efficacy and safety offered by an individual medicine, not the relative particle size, which this analysis has shown confers no additional benefit.”

Analysis Results

For the meta-analysis in adult/adolescents, treatment comparisons were made using absolute treatment differences between FP and small particle ICS medicines. The findings were as follows:

• No clinically meaningful differences were observed for a number of efficacy endpoints: Change in forced expiratory volume in 1 second (FEV1), morning peak flow and rescue medication use.

• There was a statistically significant difference favouring FP on % predicted forced expiratory flow between 25% and 75% of forced vital capacity (FEF25-75%), a known indicator of small airways function, but this was not clinically significant

• Due to the disparity of endpoints and measures used in these studies, it was not possible to include any safety data in the meta-analysis. However patients receiving FP experienced more local ICS effects than those receiving ciclesonide.

These findings show that whilst there is a known variation in the particle size of the different ICS molecules available to treat patients with asthma, this aspect of an inhaled medicine has little impact on clinical outcomes.

About asthma

Asthma is a chronic lung disease that inflames and narrows the airways, causing recurring periods of wheezing, chest tightness, shortness of breath and coughing which often occurs at night or early in the morning.1

Despite medical advances, more than half of patients continue to experience poor control and significant symptoms.2

The causes of asthma are not completely understood but likely involve an interaction between a person’s genetic make-up and the environment. Key risk factors are inhaled substances that provoke allergic reactions or irritate the airways. These include allergens such as dust mites and pets.1

Important safety Information for Seretide Salmeterol-FP Accuhaler/Diskus or Evohaler is not for relief of acute symptoms for which a fast and short-acting bronchodilator (e.g. salbutamol) is required. Patients should be advised to have their relief medication available at all times.

Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control and patients should be reviewed by a physician.

Sudden and progressive deterioration in control of asthma is potentially life-threatening and the patient should be reviewed by a physician. Consideration should be given to increasing corticosteroid therapy. Also, where the current dosage of salmeterol-FP has failed to give adequate control of asthma, the patient should be reviewed by a physician.

Treatment with salmeterol-FP should not be stopped abruptly in patients with asthma due to risk of exacerbation, therapy should be titrated-down under physician supervision. For patients with COPD cessation of therapy may be associated with symptomatic decompensation and should be supervised by a physician.

There was an increased reporting of pneumonia in studies of patients with COPD receiving salmeterol-FP (see Adverse Reactions). Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbation frequently overlap.

As with all inhaled medication containing corticosteroids, salmeterol-FP should be administered with caution in patients with active or quiescent pulmonary tuberculosis. Salmeterol-FP should be administered with caution in patients with thyrotoxicosis.

Cardiovascular effects, such as increases in systolic blood pressure and heart rate, may occasionally be seen with all sympathomimetic drugs, especially at higher than therapeutic doses. For this reason, salmeterol-FP should be used with caution in patients with pre-existing cardiovascular disease. A transient decrease in serum potassium may occur with all sympathomimetic drugs at higher therapeutic doses. Therefore, salmeterol-FP should be used with caution in patients predisposed to low levels of serum potassium.

Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods; these effects are much less likely to occur than with oral corticosteroids (see Overdosage). Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. It is important, therefore for asthma patients, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control is maintained. The possibility of impaired adrenal response should always be borne in mind in emergency and elective situations likely to produce stress and appropriate corticosteroid treatment considered (see Overdosage).

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroid is regularly monitored. Because of the possibility of impaired adrenal response, patients transferring from oral steroid therapy to inhaled fluticasone propionate therapy should be treated with special care, and adrenocortical function regularly monitored.

Following introduction of inhaled fluticasone propionate, withdrawal of systemic therapy should be gradual and patients encouraged to carry a steroid warning card indicating the possible need for additional therapy in times of stress.

There have been very rare reports of increases in blood glucose levels (see Adverse Reactions) and this should be considered when prescribing to patients with a history of diabetes mellitus. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects (see Interactions).

Data from a large US study (SMART) comparing the safety of salmeterol (a component of salmeterol-FP) or placebo added to usual therapy showed a significant increase in asthma-related deaths in patients receiving salmeterol. Data from this study suggested that African-American patients may be at greater risk of serious respiratory-related events or deaths when using salmeterol compared to placebo. It is not known if this was due to pharmacogenetic or other factors. The SMART study was not designed to determine whether concurrent use of inhaled corticosteroids modifies the risk of asthma-related death. (see Clinical Studies)

It was observed in a drug interaction study that concomitant use of systemic ketoconazole increases exposure to salmeterol. This may lead to prolongation in the QTc interval. Caution should be exercised when strong CYP3A4 inhibitors (e.g. ketoconazole) are co-administered with salmeterol. (see Interactions, and Pharmacokinetics).

As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with a fast and short-acting inhaled bronchodilator. Salmeterol-FP Accuhaler/Diskus or Evohaler should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.(see Adverse Reactions) The pharmacological side-effects of beta-2 agonist treatment, such as tremor, subjective palpitations and headache have been reported, but tend to be transient and to reduce with regular therapy. (see Adverse Reactions)

GSK – one of the world’s leading research-based pharmaceutical and healthcare companies – is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For further information please visit www.gsk.com.

GSK enquiries:

Claire Brough
+44 (0) 7920 567 507
(London)

Eleanor Craven
+44 (0) 7876 870 271
(London)

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