About COPD

COPD is an inflammatory disease with systemic effects, and is characterised by airflow obstruction that is usually progressive and not fully reversible.2,6 The obstruction is confirmed by spirometry that shows a post-bronchodilator FEV₁/FVC ratio below 0.7 (where FEV₁ is forced expiratory volume in 1 second and FVC is forced vital capacity).2 Severity is then assessed by comparing the measured FEV₁ to the value predicted (based on height, sex, age and ethnicity) (see Table).

What is roflumilast?

Roflumilast is an anti-inflammatory drug that acts by inhibiting PDE4, an enzyme found in structural and inflammatory cells, including those important in the pathogenesis of COPD.5 This inhibition raises concentrations of intracellular cyclic adenosine monophosphate and thereby mitigates COPD-related malfunction of various cells, in experimental models. Theophylline, a non-selective PDE inhibitor, also inhibits PDE4 and has anti-inflammatory actions. Whether roflumilast's action differs from theophylline in clinical practice is unclear.

The summary of product characteristics (SPC) states that roflumilast is indicated as an add-on to bronchodilator therapy for maintenance treatment in severe COPD (post-bronchodilator FEV₁ less than 50% predicted) associated with chronic bronchitis in adults with a history of frequent exacerbations. Chronic bronchitis is defined as productive cough on most days for at least 3 months for 2 consecutive years.7 The licensed dose is one 500µg tablet daily.5 The SPC states that roflumilast “may need to be taken for several weeks to achieve its effect”.

Clinical evidence

In one double-blind randomised controlled trial, 1,514 patients with severe or very severe COPD (National Institute for Health and Clinical Excellence [NICE] stage 3 or 4) received either roflumilast 500µg or placebo daily, for 1 year.8 Prior to randomisation, patients underwent a 4-week single-blind run-in period, during which they received placebo (and salbutamol as rescue medication). They were only randomised to the study if they had adhered to this regimen and were clinically stable (e.g. with no exacerbation or lower respiratory tract infection). A total of 315 patients (out of 1,829) were withdrawn at this stage. Inhaled corticosteroids (equivalent to beclometasone 2mg or less) and short-acting antimuscarinics were allowed at a constant daily dose if patients had already been using them before the trial; however, LABAs, LAMAs and combination inhaled therapy were not allowed. All patients could take salbutamol as rescue medication. Primary outcome measures were the change from baseline to endpoint in post-bronchodilator FEV₁ and the number of moderate or severe exacerbations per patient per year. (Moderate exacerbations were defined as symptomatic deteriorations treated with systemic corticosteroids and/or antibiotics; severe events were those requiring hospitalisation.) At 52 weeks, mean post-bronchodilator FEV₁ had improved with roflumilast (by 12mL, from 1,131mL), while it had deteriorated (by 26mL, from 1,145mL) with placebo (quoted difference 39mL, p<0.001). However, the rate of moderate or severe exacerbations did not differ significantly between the two groups (0.86 per patient per year with roflumilast vs. 0.92 per patient per year with placebo, p=0.451). More patients in the roflumilast group withdrew from the study due to adverse events such as diarrhoea, nausea or headache (14% vs. 7% with placebo).

The results of two identically designed double-blind randomised placebo-controlled trials in two different populations were pooled and published together.9 They involved a total of 3,096 patients with severe COPD and chronic cough and sputum production, who received either roflumilast 500µg or placebo daily, for 1 year, after a 4-week run-in period with a placebo tablet. To continue in the trial, participants needed to fulfil several criteria, including having 80% minimum adherence during the run-in and being “clinically stable”. A total of 1,419 people were not randomised after this stage. Patients could use short-acting beta₂ agonists and continue with LABAs or short-acting antimuscarinics “at stable doses”, but LAMAs and inhaled corticosteroids were not permitted. Primary outcome measures were change in pre-bronchodilator FEV₁ during treatment and rate of COPD exacerbations that were either moderate (i.e. requiring oral or parenteral corticosteroids) or severe (i.e. associated with hospital admission or death). Mean pre-bronchodilator FEV₁ increased by 40mL (from 1,010mL) in the patients taking roflumilast compared with a mean decrease in the placebo group of 9mL (from 1,020mL; difference between groups stated as 48mL, p<0.001). There was also a lower rate of moderate or severe exacerbations in the roflumilast group compared to placebo (1.14 vs. 1.37 per year, relative risk 0.83, 95% CI 0.75 to 0.92). The discontinuation rate was higher with roflumilast, as was the rate of withdrawal due to adverse events (e.g. diarrhoea, nausea, headache) in the first 12 weeks (8% vs. 3% with placebo). A mean weight loss of 2.09kg occurred in the roflumilast group compared with an increase of 0.08kg with placebo.

In a third report, in which another two double-blind randomised placebo-controlled trials were published together, patients with stable moderate to severe COPD were allocated to roflumilast 500µg or placebo daily, plus (in one study) salmeterol (933 patients) or (in the other study) tiotropium (743 patients), for 24 weeks.10 Importantly, there were differences in the inclusion criteria for the two trials. Patients recruited to the roflumilast or placebo plus tiotropium trial were required to have chronic cough and sputum production, and frequent use of as-needed short-acting beta₂ agonists (at least 28 puffs per week) during the run-in period. This was not required in the roflumilast or placebo plus salmeterol trial. Consequently, the authors stated that the designs of the studies did not allow comparison of efficacy and safety between the roflumilast plus salmeterol and roflumilast plus tiotropium treatment combinations. Patients were randomised if they took at least 80% of the prescribed placebo medication (which they were blinded to) in the 4-week run-in period. A total of 452 were not randomised after this stage. The primary outcome measure in both trials was change in mean pre-bronchodilator FEV₁ from baseline to each post-randomisation visit. Apart from the prescribed salmeterol or tiotropium, no other respiratory medications were allowed after enrolment. In the roflumilast or placebo plus salmeterol trial, the mean change in pre-bronchodilator FEV₁ was 49mL in favour of the roflumilast group (+39mL from 1,430mL vs. −10mL from 1,410mL with placebo, p<0.0001). In the roflumilast or placebo plus tiotropium trial, the mean change was reported as 80mL in favour of the roflumilast group (+65mL from 1,470mL vs. −16mL from 1,490mL with placebo, p<0.0001). Fewer patients in the roflumilast groups had exacerbations (mild, moderate or severe) than in the respective placebo comparator groups (for roflumilast plus salmeterol vs. placebo plus salmeterol the risk ratio [RR] for an exacerbation was 0.82, 95% CI 0.68 to 0.99; for roflumilast plus tiotropium vs. placebo plus tiotropium the RR was 0.75, 95% CI 0.59 to 0.95). There was significant weight loss in each of the roflumilast groups compared to the placebo groups (−2.0kg vs. +0.2kg in the roflumilast plus salmeterol group and −1.8kg vs. +0.3kg in the roflumilast plus tiotropium group).

Unwanted effects and cautions

The SPC states that common unwanted effects (i.e. occurring in 1 in 100 to 1 in 10 patients) with roflumilast include headache, insomnia, decreased weight, decreased appetite, diarrhoea, nausea and abdominal pain.5 Uncommon unwanted effects (i.e. occurring in 1 in 1,000 to 1 in 100 patients) include hypersensitivity, anxiety, tremor, vertigo, dizziness, palpitations, gastritis, vomiting, gastro-oesophageal reflux disease, indigestion, rash, back pain, muscle spasms and weakness, myalgia and fatigue. The SPC states that rare instances of suicidal thinking and behaviour (including completed suicide) have been reported in clinical studies, and so does not recommend the drug for patients with a history of depression associated with suicidal ideation or behaviour.

The SPC recommends against using roflumilast in pregnant women or in women of child-bearing age not using contraception or those who are breastfeeding.5 It also states that no dose alteration is required for those aged 65 years or above or with renal impairment. For those with mild hepatic impairment (Child-Pugh A), the SPC advises that “the clinical data are insufficient… to recommend a dose adjustment”. However, it says that roflumilast is contraindicated in those with moderate or severe hepatic impairment (Child-Pugh B or C). It also states that treatment should not be initiated, or existing treatment should be stopped, in patients with severe immunological diseases, severe acute infections diseases, or cancer.

The SPC recommends against concomitant treatment with theophylline. Administration of the cytochrome P450 enzyme-inducer rifampicin reduced total PDE4 inhibitory activity by about 60%; consequently, the SPC states that the use of strong cytochrome P450-inducers (e.g. carbamazepine, phenobarbital, phenytoin) may reduce the therapeutic efficacy of roflumilast.

What guidelines say

NICE has not issued any guidance on roflumilast. The Scottish Medicines Consortium (SMC) has concluded that while “roflumilast has been associated with improved lung function and reduced the rate of moderate and severe COPD exacerbations compared to placebo in studies of patients representing the licensed population. The manufacturer did not present a sufficiently robust economic analysis to gain acceptance by SMC”.11 In 2010, the Pulmonary-Allergy Drugs Advisory Committee to the US Food and Drug Administration voted against licensing roflumilast. Most of the members who voted against licensing considered that “drug efficacy is present, but not strong; benefits are meager; benefit does not outweigh the safety profile of the drug; and place in therapy is still unknown”.12

Costs

The annual cost to the NHS of roflumilast 500µg orally once daily is around £460.