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Roflumilast (DAXAS) ® in the management of severe chronic obstructive pulmonary disease

Lead author: Neil Frankland Lead Pharmacist for Medicines Management NHS Regional Drug & Therapeutics Centre (Newcastle) June 2010 ©NETAG 2010

Roflumilast (Daxas®) for COPD

NETAG

Summary · Roflumilast (Daxas®) is a first-in-class oral once-daily phosphodiesterase type-4 inhibitor licensed for the treatment of chronic obstructive pulmonary disease (COPD) in patients with chronic bronchitis as add-on to bronchodilator therapy. · It has been evaluated in a series of robust placebo-controlled phase III clinical studies involving in excess of 5,000 patients with follow-up of up to one year. Roflumilast has demonstrated modest improvements in lung function and reduced health care utilisation such as ancillary medication (e.g. steroids and antibiotics), exacerbations, and hospital admissions. · There is a particular lack of evidence relating to use of roflumilast in patients who are also using inhaled steroids. · Roflumilast presents a significant burden of adverse effects compared with placebo. The most frequent effects include diarrhoea, weight loss, decreased appetitie, nausea and headache. Cessation of therapy due to roflumilast was common in studies although only slightly greater than with placebo. Of concern was an observed small increased risk of malignancy. · The cost of roflumilast is not currently known but it is estimated to cost about the same as tiotropium at about £40 per month or £480 per patient per annum. It is not easy to estimate what the potential uptake of roflumilast might be given its licensed indication, however estimates range from 550 to up to 2,500 patients within NHS North East. · Roflumilast is likely to represent an additional cost to the pharmaceutical management of COPD even if maximal offset costs from reduced use of other medication and health care utilisation are factored in. · Roflumilast offers a new treatment with convenient administration and a unique pharmacology. There is particular unmet need in COPD in patients who are on maximal doses of standard therapies but still experience frequent exacerbations. However roflumilast has not been specifically investigated in this patient group.

North East Treatment Advisory Group, June 2010 2

Rofllumilast (Daxas®) for COPD

NETAG

Introduction Roflumilast (Daxas®, Bristol-Myers Squibb) is a first-in-class oral phosphodiesterase-4 (PDE4) inhibitor. PDE4 is a key enzyme responsible for upregulation of immune and inflammatory cells such as neutrophils, lymphocytes and macrophages often involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). 1,2 Therefore inhibition of PDE4 in the context of COPD provides an anti-inflammatory action as well as other possible positive effects such as relaxation of airway smooth muscle and modulation of pulmonary nerves. 1 Roflumilast will be licensed for `maintenance treatment of severe COPD associated with chronic bronchitis in adult patients with a history of frequent exacerbations as add on to bronchodilator treatment'. The licensed dose will be roflumilast 500 micrograms, one tablet daily. COPD is a chronic inflammatory disease characterised by progressive expiratory airflow limitation that is non- or poorly reversible. 1 The predominant symptoms of COPD are a chronic sputum-producing cough and shortness of breath on exertion. Recent prevalence data for NHS North East identifies 61,300 diagnosed cases of COPD accounting for 2.3% of the registered general practice population. Due to historical social and environmental factors, NHS North East has the highest COPD prevalence of any English health authority. 3 Currently there is no treatment available that alters the course of COPD and therefore the aim of treatment is on improving symptoms and functional status. Treatment for COPD differs according to the stability and severity of the disease. Pharmacotherapy for stable patients is mainly based on use of various inhaled agents such as short- and long-acting bronchodilators as single or combined therapy with or without inhaled corticosteroids. 4 The mainstay of treatment is the inhaled bronchodilators which includes short- and long-acting beta-adrenoceptor agonists (SABA and LABA) and antimuscarinic drugs. Examples include salbutamol, salmeterol and tiotropium, respectively. 4 Bronchodilators produce relatively small and transient changes in FEV1 but remain an important therapeutic choice because they have positive effects on symptoms such as breathlessness and shortness of breath. Inhaled corticosteroids are often used in combination with long-acting bronchodilators for more severe disease. The use of oral medication in COPD is generally limited to theophylline and short courses of oral steroids. Theophylline is not commonly used due to modest efficacy, adverse effects and a narrow therapeutic window. The North East Treatment Advisory Group has been requested by a member decision drug and therapeutics group to conduct an appraisal of, and issue a recommendation for, the use of roflumilast within its licensed indication.

North East Treatment Advisory Group, June 2010

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Rofllumilast (Daxas®) for COPD

NETAG

Clinical evidence The clinical development program for roflumilast in COPD was extensive and included four large placebo-controlled randomised studies of between six and 12 months duration. All patients were former or current smokers. 5,6 Two 12-month trials of identical design compared roflumilast 500 micrograms daily with placebo in patients with severe COPD. Patients were aged 40 years with FEV1 50% predicted and at least one recorded exacerbation in the previous 12 months. The trials were of identical design except that one consisted of an almost exclusively white population and the other, although still predominantly white, had about one fifth of patients from Asian populations. Other than ethnic origin, all baseline parameters were similar. During the study patients were not permitted to use inhaled corticosteroids and only about half of patients used a long-acting bronchodilator. The results reported here are of a pooled analysis with 1,537 patients randomised to roflumilast and 1,554 to placebo. The primary outcome measures were the change in pre-bronchodilator FEV1 and the rate of COPD exacerbations (defined as moderate if requiring only corticosteroids or severe if resulting in hospital admission or death) from baseline to 52 weeks. Prebronchodilator FEV1 increased by 40 ml with roflumilast and decreased by 9 ml with placebo, a difference of 48 ml (p < 0.0001). Post-bronchodilator FEV1 changes were similar (difference 55 ml, p < 0.0001). The rate of exacerbations that were moderate or severe per patient per year was 1.14 with roflumilast compared to 1.37 with placebo (relative risk reduction of 17%; p = 0.0003). Separately, the difference in exacerbations was greatest for moderate exacerbations and was not statistically significant for severe exacerbations. 5 The two six-month studies provide evidence for use of roflumilast 500 micrograms daily as add-on therapy to inhaled long-acting bronchodilators. Again, the two studies were very similar in design except that in one roflumilast was added to salmeterol (n = 933) and in the other to tiotropium (n = 743). In addition, the tiotropium patients tended to have more severe disease. Patients were aged 40 years with moderate to severe COPD (FEV1 40 to 70% predicted) and were not permitted to use inhaled corticosteroids. The primary outcomes measure was the change in pre-bronchodilator FEV1 from baseline to week 24. In the salmeterol study 467 patients were randomised to roflumilast and 468 to placebo, and in the tiotropium study 372 were randomised to roflumilast and 372 to placebo. After 24 weeks of treatment in the salmeterol study pre-bronchodilator FEV1 had increased by 39 ml in roflumilast patients and decreased by 10 ml in placebo patients, a difference of 49 ml (p < 0001). In the tiotropium study FEV1 increased by 65 ml in roflumilast patients and decreased by 16 ml in placebo patients, a difference of 80 ml (p < 0.0001). Similar improvements in post-bronchodilator FEV1 were noted in both groups. The all-exacerbation rate per patient per annum (defined as mild if required increase in rescue medication of 3 puffs per day on 2 consecutive days; moderate if required oral corticosteroids and severe if treated in hospital or death) was about 1.9 in roflumilast patients and 2.3 in placebo patients (combined p-value not provided, individual p > 0.05). The moderate plus severe combined exacerbation rate is not reported. 6

North East Treatment Advisory Group, June 2010

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Rofllumilast (Daxas®) for COPD

NETAG

In addition to these four studies, roflumilast has been evaluated in a one-year placebo-controlled double-blind randomised study in which about half of patients were using concomitant inhaled steroid therapy and more than a quarter were using an oral xanthine as well as other therapies. Patients with severe (FEV1 50% predicted) were randomised to 52 weeks treatment with roflumilast (n = 760) or placebo (n = 753) as well as stable doses of their regular medication. However, these patients did not necessarily have a history of chronic bronchitis or previous exacerbations. The primary outcome measures were the change from baseline in post-bronchodilator FEV1 and the number of moderate or severe exacerbations per patient per annum. At 52 weeks, FEV1 had improved by 12 ml in the roflumilast group and decreased by 26 ml in the placebo group, a difference of 39 ml (p = 0.001). Moderate or severe exacerbations were not significantly different with 0.9 per patient per annum in each group. 7 Safety Excluding the primary diagnosis of COPD, the most common adverse effects encountered in the four key efficacy studies were, roflumilast vs. control respectively: diarrhoea (~10% vs. 3%), weight loss (~10% vs. 3%), nasopharyngitis (all ~6 to 7%), upper respiratory tract infection (all ~ 3 to 5%), headache (~3% vs. 1%), nausea (~3 to 5% vs. 2%), decreased appetite (~3% vs. < 1%), back pain (all ~ 2 to 4%), influenza (all ~ 2 to 4%), hypertension (all ~ 2 to 4%) and acute bronchitis (all ~ 3 to 5%). The adverse effect profiles were consistent across these studies and with earlier studies of roflumilast. Discontinuations from clinical studies due to adverse events were generally higher in roflumilast groups than in placebo groups. Other than COPD, the most common reasons cited for withdrawal were diarrhoea, nausea and headache. The difference in discontinuation rates due to adverse effects in the one-year studies yields a number-needed-to-harm of 35 (i.e. for every 35 patients treated with roflumilast instead of placebo an additional patient will cease treatment with roflumilast). Table 1. Most common adverse events observed in key roflumilast studies

Reference Treatment Diarrhoea Nausea Weight loss Headache Influenza

Nasopharyngitis

Placebo (n = 790) 5 Roflumilast (n = 778) Placebo (n = 755) Roflumilast (n = 769) 6 Salmeterol 6 Tiotropium Placebo (n = 467) Roflumilast (n = 466) Placebo (n = 369) Roflumilast (n = 374)

3% 9%* 3% 8%* 3% 8%* <1% 9%*

2% 3% 2% 5%* <1% 5%* 1% 3%

3% 8%* 3% 12%* 1% 12%* <1% 6%*

1% 3%* 2% 3% 1% 3% 0% 2%*

3% 2% 2% 4% 2% 4% 0% <1%

7% 5% 7% 7% 7% 7% 5% 6%

* p < 0.05 vs. Placebo

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Rofllumilast (Daxas®) for COPD

NETAG

An increased incidence of malignancies has been observed in patients treated with roflumilast compared with patients treated with placebo, as demonstrated in table 2. The overall numbers of patients affected are small, and the differences only become statistically significant when looking at some specific types of cancer for which patient numbers are smaller still. Nonetheless, the trend is consistent across cancer types and there is a biological plausibility for this effect based on the drugs pharmacological profile. Table 2. Rates of malignancies observed in a pooled analysis of clinical studies 8

Roflumilast (n = 5,752)

Tumours % Annual incidence rate

Placebo (n = 5,505)

Tumours % Annual incidence rate

p

All malignancies All excl. Skin Lung Prostate Colorectal

93 80 29 13 9

1.62 1.39 0.50 0.23 0.16

0.0292 0.0255 0.0096 0.0046 0.0027

73 61 17 5 2

1.33 1.11 0.31 0.09 0.04

0.0235 0.0206 0.0074 0.0013 0.0004

0.058 0.053 0.047 0.045 0.028

p values for difference between roflumilast and placebo (log-rank test)

North East Treatment Advisory Group, June 2010

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Rofllumilast (Daxas®) for COPD

NETAG

Cost analysis The price of roflumilast is not currently known. For the purpose of this evaluation it has been assumed it will have a similar monthly cost as tiotropium, the most recent new chemical entity licensed for the treatment of COPD. Therefore it is assumed roflumilast will cost £40 per month, or £480 per annum, per patient. Roflumilast will be licensed only for patients with severe disease and chronic bronchitis and a history of frequent exacerbations. It is not known what proportion of the COPD patient population that this definition would relate to. However evidence from several sources indicates that about 30 to 50% of diagnosed cases of COPD are categorised as severe and that a history of frequent exacerbations and chronic bronchitis is common in this group. Therefore, for the purpose of this evaluation, it is assumed that 40% of all COPD patients will meet the licensed indication for treatment with roflumilast, corresponding to a maximum patient population of 25,000 within NHS North East It is not clear how frequently roflumilast would be used in this patient group, particularly given the widespread use of inhaled steroids and the paucity of evidence relating to concomitant roflumilast and steroid therapy. The use of xanthine drugs (aminophylline and theophylline), alternative oral drugs licensed for COPD, indicates that oral therapies are not commonly used in COPD. However roflumilast may be used more frequently than the xanthine drugs because it does not require frequent monitoring and has once daily dosing compared with typical twice-daily dosing for xanthines. In addition, xanthines are also licensed for the treatment of asthma and licensed in children although they are not commonly used for this indication and therefore not commonly prescribed for children. Where possible, proprietary brands licensed specifically for asthma have been excluded from calculations. Nonetheless, it will be assumed that current prescribing of xanthines can serve as a model for the potential uptake of roflumilast. In addition, the current recommendation from NICE for the use of xanthines (theophylline) is similar to the licensed indication for roflumilast with respect to combined use with bronchodilators: 9 `Offer [theophylline] only after trials of short- and long-acting bronchodilators or to people who cannot use inhaled therapy. Theophylline can be used in combination with beta2 agonists and muscarinic antagonists.' Based on average daily doses, 10 within NHS North East in the year April 2009 to March 2010 a total of 1.824 million days of therapy of oral xanthine drugs was prescribed for COPD in primary care at a cost of £171,000. 11 This equates to an assumption that 5,000 patients with COPD within NHS North East are treated with oral xanthines, equating to 8% of COPD patients. If the use of xanthines was directly converted to use of roflumilast the resulting cost would be £2.4 million. However, if it is assumed that demand for oral drugs in COPD is subsequently shared between xanthine drugs and roflumilast and that roflumilast accounts for

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Rofllumilast (Daxas®) for COPD

NETAG

50% of this use then the total cost of roflumilast would be £1.2 million and the total cost would be £1.285 million. 12,13 An analysis of the rate of uptake of roflumilast published by Nycomed is more conservative and estimates that 10% of eligible patients would be treated with roflumilast after two years. This equates to about 550 patients within NHS North East at a total annual cost of £264,000. 14 The estimates relating to the uptake of roflumilast should be interpreted as the possible long-term impact because there will probably be a lag period between the drug becoming available and the attainment of a steady level of prescribing as predicted. Some costs can be offset against the use of roflumilast. Direct offset costs may include: 1. Substitution of use of xanthine drugs 2. Reduced use of oral steroids, oral antibiotics and inhaled rescue medication (principally inhaled salbutamol) 3. Reduced exacerbations including reduced admissions to hospital Evidence from the 12-month studies of roflumilast indicates that use of steroids or antibiotics is reduced by 16% (i.e. for every nine patients treated with roflumilast there is a reduction of two prescriptions for steroids or antibiotics per annum). 5 In terms of direct costs, this reduction is unlikely to yield significant offset savings as oral steroids and antibiotics are typically prescribed for only a short duration (one or two weeks) and are inexpensive treatments. As indicated previously, savings from substitution with xanthine drugs is also unlikely to yield significant savings as these drugs have typical monthly costs of between £3 and £5 (regional mean £3.50) depending on the actual product. However this does not include the cost of theophylline monitoring. 13 Evidence from the12-month phase III studies indicates that the annual severe exacerbation rate resulting in hospitalisation or death is reduced from 15 to 12 per 100 patients, an absolute reduction of 3 per 100 patients, or a number-neededtreat of 34 (i.e. you would need to treat 34 patients with roflumilast for one year to prevent one acute hospital admission). The current payment-by-results tariff price for an emergency admission to an accident and emergency department is £87. If a patient is subsequently admitted to a hospital ward the tariff price is £632 for stays of up to three days with each additional day incurring a charge of £200. Thus for a non-elective emergency admission of 3 days the cost is £719. This does not include any subsequent care that might be provided, for example diagnostic and imaging procedures. NICE guidelines for the management of COPD indicate that the total cost to the NHS for a severe exacerbation is between £1,400 and £1,600 per patient. The cost of treating 34 patients with roflumilast for one year is estimated at about £16,000. Balanced against these off-set costs are costs that will likely be incurred from managing the adverse effects of roflumilast. These costs will arise through medical consultation, prescriptions for symptomatic relief, medicine wastage and even hospital admission. It has not been possible to reliably estimate the cost of

North East Treatment Advisory Group, June 2010 8

Rofllumilast (Daxas®) for COPD

NETAG

managing adverse effects although their net burden per patient would probably be small due to their nature and frequency. Note these figures do not include an estimate of the cost in secondary care as it is expected that the majority of the prescribing would occur within primary care. Evidence from the 12-month studies indicates that, compared with placebo in patients not taking inhaled steroids or tiotropium, roflumilast is associated a minimal non-significant increase in quality of life as measured by the EuroQol fivedimension survey. Given that the there is no evidence for any significant changes in quality of life and the absence of evidence for an effect on survival when compared with placebo, it is assumed that roflumilast provides no loss or gain in quality-adjusted life years (QALYs). Considering that roflumilast is likely to present an additional cost burden even if maximal offset costs are counted, roflumilast is unlikely to meet conventional limits for cost-effectiveness based on QALYs.

North East Treatment Advisory Group, June 2010

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Roflumilast (Daxas®) for COPD

NETAG

Table 3. Estimated annual cost to NHS North East organisations of treating patients with roflumilast for COPD. NHS North East population 20.0% 3.8% 10.2% 8.0% 12.1% 7.5% 5.9% 10.7% 3.6% 5.6% 7.4% 5.2% 100% 551 patients: £264,480 2,501 patients: £1,200,480 120 patients: £57,600 544 patients: £261,120 133 patients: £63,840 603 patients: £289,440 Estimated annual number of patients, and associated cost, if total patient population is `n' 550* 131 patients: £62,880 167 patients: £80,160 2,500** 596 patients: £286,080 758 patients: £363,840

Primary Care Cluster

Primary Care Trust County Durham Darlington Newcastle North Tyneside Northumberland Gateshead

Durham and Darlington

North of Tyne

South of Tyne

South Tyneside Sunderland Hartlepool Middlesbrough North Tees Redcar & Cleveland

Tees

NHS North East total

: Assumed cost of treatment is £40 per one month pack; £480 per patient per annum. : GP registered populations 2009, NHS Information Centre. www.ic.nhs.uk/statistics-and-data-collections/population-and-geography/gp-registered-populations 14 * : Estimate of 550 patients taken from budget impact assessment published by Nycomed. ** : Estimate of 2,500 based on half of the estimated number of patients treated with oral xanthine drugs for COPD. Costs demonstrated do not include potential off-set cost from reduced use of oral xanthine drugs.

North East Treatment Advisory Group, June 2010

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Roflumilast (Daxas®) for COPD

NETAG

Points to consider Roflumilast has been extensively studied in large numbers of COPD patients with study duration of up to one year. Results consistently demonstrate a modest benefit for roflumilast compared with placebo in terms of improved lung function (FEV1) and reduced exacerbations. However, a one year observation period is a short period of time to accurately assess changes in FEV1, the majority of exacerbations were mild or moderate and the studies were not powered to identify differences in individual categories of exacerbation. None of the key studies permitted concomitant use of inhaled steroid therapy, a treatment that would likely be used by the majority of eligible patients. It is therefore not clear what effect roflumilast will have if it is used in combination with inhaled steroids. It has demonstrated similar efficacy when added to single longacting bronchodilator therapy as it has when compared with placebo, although it has not been compared to dual bronchodilator therapy with a LABA and an antimuscarinic. In one study that did permit concomitant use of inhaled steroids the rate of hospital admission was low in both groups and did not demonstrate any difference between roflumilast and placebo. Roflumilast presents a significant burden of adverse effects although the majority appear to be of mild intensity and there is evidence that they may subside over time. In the one-year studies, 14% of patients treated with roflumilast withdrew due to adverse effects. The longer term safety profile of roflumilast is not known and there are appreciable concerns regarding an increased incidence of malignancy. Compared with existing oral treatments for COPD, roflumilast provides an alternative with a unique pharmacology and convenient once-daily dosing. There is no evidence that roflumilast has a significant impact on overall quality of life or survival. It is estimated that it will cost £40 per month, which would make it one of the most costly single-ingredient treatments for COPD. It has not been possible to accurately estimate the potential patient population based on the licensed indication however given the relatively high incidence of COPD within NHS North East it is likely to be substantial. The US Food and Drug Administration (FDA) rejected a license application for roflumilast in COPD. Concerns were raised about the number of patients discontinuing therapy because of adverse events and about an observed increased incidence of cancer. Current treatment for COPD is defined by national guidelines. There is unmet clinical need for patients who cannot use inhaled steroids and for those who still experience an excess of exacerbations despite therapy with inhaled steroids and long acting bronchodilators. Author's declarations: The lead author has no relevant interests to declare. The secondary author (William Horsley, Lead Pharmacist for NETAG) has participated in several non-promotional educational meetings and two advisory boards for a pharmaceutical company with a significant respiratory product portfolio.

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Rofllumilast (Daxas®) for COPD

NETAG

References

1. Vignola AM. PDE4 inhibitors in COPD- a more selective approach to treatment. Respir. Me. 2004;98:495-503 2. Baker EL, Baker L. roflumilast: a new phosphodiesterase 4 inhibitor for chronic obstructive pulmonary disease. Formulary. 2010; 45:6-13. 3. NHS Information Centre. Unadjusted disease prevalence: Quality and outcomes framework (QOF) for April 2007 ­ March 2008, England. Numbers of QOF disease registers and unadjusted prevalence rates by Strategic Health Authority. www.ic.nhs.uk/webfiles/QOF/2007-08/NewFilesGS/QOF0708_SHAs_Prevalence.xls 4. National Clinical Guideline Centre. (2010) Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary care and secondary care. London: National Clinical Guideline Centre. http://guidance.nice.org.uk/CG101/Guidance/pdf/English 5. Calverley PMA, Rabe KF, Goehring U-M et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009;374:685-94 6. Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, Bundschuh DS et al. Roflumilast in moderateto-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 2009;374:695-703 7. Calverley PMA, Sanchez-Toril F, McIvor A et al. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 2007;176:154-61 8. Analysis of Malignancy for Roflumilast 500 micrograms Group vs Placebo. FDA. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary -AllergyDrugsAdvisoryCommittee/UCM208710.pdf. Accessed 11.5.2010. 9. National Institute for Health and Clinical Excellence. Clinical guideline 101: Management of chronic obstructive pulmonary disease in adults in primary and secondary care (update of NICE clinical guidelines 12). Quick reference guide. London, June 2010. 10. Average daily quantities. NHS Information Centre. April 2009. www.ic.nhs.uk/webfiles/Services/PSU/adqs_2009_10.pdf 11. Data on file. NHS Regional Drug & Therapeutics Centre (Newcastle). June 2010. 12. Data provided by the Regional Drug & Therapeutics Centre, Newcastle. Primary care prescribing for NHS North East, April 2009 to March 2010 (inclusive). www.nyrdtc.nhs.uk 13. NHS dictionary of medicines and devices. www.dmd.nhs.uk Accessed June 2010. 14. Anon. Prescribing impact resource template for roflumilast (Daxas®) for chronic obstructive pulmonary disease (COPD): A resource for NHS budget holders. Nycomed, May 2010.

Appendix 1. Measurement of lung function ­ FEV1 Lung function is measured in a number of ways. One commonly used measurement is the FEV1, the `forced expiratory volume in one second'. This is measured using the technique of spirometry and is a measure, in litres, of the volume of air that can be forcibly exhaled by a subject in the first second of expiration. Normal values for a healthy young adult male would be about five or more litres. The value is often expressed as measure of the predicted value based on the patient's age, sex, and height. The predicted FEV1 is presented as a percentage of the predicted score. In patients with COPD this is always less than 100%. The latest version of NICE guidance differs in classification of COPD from the previous 2004 version. Now, a predicted FEV1 between 30 and 50% is indicative of severe disease, between 50 and 70% is moderate disease and 80 % is mild disease. 10

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Roflumilast (DAXAS) in the management of severe chronic obstructive pulmonary disease