Which Patients Benefit Most From Roflumilast?
Which patients would benefit most from roflumilast therapy for the management of chronic obstructive pulmonary disease (COPD)?
Roflumilast was approved in 2011 for COPD exacerbation reduction in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. This oral phosphodiesterase-4 (PDE4) inhibitor is thought to exert its pharmacologic action by increasing cyclic adenosine monophosphate in lung tissues and cells leading to an overall anti-inflammatory effect. Currently, roflumilast is noted in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines as an appropriate add-on to a long-acting bronchodilator in patients with forced expiratory volume in 1 second (FEV1) < 50% predicted, chronic bronchitis, and frequent exacerbations.
In combination with salmeterol or tiotropium, roflumilast was shown to improve prebronchodilator FEV1, prolong median time to first exacerbation, and reduce the overall exacerbation rate. Reduction of dyspnea severity, improved health-related quality of life, and reduction in rescue medication use were also noted. Patients with severe and very severe COPD, defined as a postbronchodilator FEV1 < 50%, had improved prebronchodilator FEV1 and a reduction in exacerbations per year when roflumilast was added to short- and long-acting beta-2 agonists.
Specific subsets of patients who were identified in post-hoc pooled analyses showed significant reduction in exacerbations in those with chronic bronchitis, with a greater effect on exacerbation reduction in patients who were using inhaled corticosteroids (ICSs). Of note, the beneficial effects of roflumilast in patients with chronic bronchitis are equivalent to those seen in patients receiving ICS in combination with long-acting bronchodilators.
Secondary to the treatment guideline recommendations, COPD patients are typically on either dual or triple therapy including a long-acting beta-2 agonist, long-acting anticholinergic, and/or an ICS. Therefore, the importance of evaluating roflumilast's place in combination with the standard of care is necessary before patients are routinely prescribed this new drug therapy. The Roflumilast in the Prevention of COPD Exacerbations While Taking Appropriate Combination Treatment (REACT) study protocol was recently published to address this gap in the literature by evaluating whether the addition of roflumilast to inhaled combination therapy further reduces exacerbations in patients who are having frequent exacerbations despite optimized treatment.
Of additional interest regarding roflumilast therapy, evaluation of specific patient subset responders to this medication verifies the concept that there are different phenotypes of COPD. In the evolving world of personalized medicine, identifying those patient subgroups who respond to PDE4 inhibitors may allow for more targeted therapies in patients with certain phenotypes. Patients with a frequent exacerbator phenotype, defined as > 2 exacerbations per year, benefited from roflumilast therapy independent of long-acting bronchodilator or ICS use. These patients shifted from being frequent exacerbators to more stable infrequent exacerbators, which can be extrapolated to conclude that the anti-inflammatory effects of roflumilast can stabilize the disease in frequent exacerbator phenotypes. The different mechanism of action of this agent compared with current COPD treatment options has the potential to provide additive benefits in the management of COPD.
Adverse effects associated with roflumilast include diarrhea, weight loss, nausea, anxiety/depression, and headache. From clinical trial evaluations of these effects, associated diarrhea, nausea, and headache seem to be transient, but weight loss is maintained throughout roflumilast treatment. Patients should be evaluated for their ability to tolerate weight loss (as much as 2 kg has been reported) as well as underlying neuropsychiatric disorders prior to initiating roflumilast treatment. Of course, study results from the REACT trial will provide more prospective data about the clinical significance of such side effects.
Question
Which patients would benefit most from roflumilast therapy for the management of chronic obstructive pulmonary disease (COPD)?
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Response from Nancy Hope Goodbar, PharmD Assistant Professor of Pharmacy Practice, Presbyterian College School of Pharmacy, Clinton, South Carolina |
Roflumilast was approved in 2011 for COPD exacerbation reduction in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. This oral phosphodiesterase-4 (PDE4) inhibitor is thought to exert its pharmacologic action by increasing cyclic adenosine monophosphate in lung tissues and cells leading to an overall anti-inflammatory effect. Currently, roflumilast is noted in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines as an appropriate add-on to a long-acting bronchodilator in patients with forced expiratory volume in 1 second (FEV1) < 50% predicted, chronic bronchitis, and frequent exacerbations.
In combination with salmeterol or tiotropium, roflumilast was shown to improve prebronchodilator FEV1, prolong median time to first exacerbation, and reduce the overall exacerbation rate. Reduction of dyspnea severity, improved health-related quality of life, and reduction in rescue medication use were also noted. Patients with severe and very severe COPD, defined as a postbronchodilator FEV1 < 50%, had improved prebronchodilator FEV1 and a reduction in exacerbations per year when roflumilast was added to short- and long-acting beta-2 agonists.
Specific subsets of patients who were identified in post-hoc pooled analyses showed significant reduction in exacerbations in those with chronic bronchitis, with a greater effect on exacerbation reduction in patients who were using inhaled corticosteroids (ICSs). Of note, the beneficial effects of roflumilast in patients with chronic bronchitis are equivalent to those seen in patients receiving ICS in combination with long-acting bronchodilators.
Secondary to the treatment guideline recommendations, COPD patients are typically on either dual or triple therapy including a long-acting beta-2 agonist, long-acting anticholinergic, and/or an ICS. Therefore, the importance of evaluating roflumilast's place in combination with the standard of care is necessary before patients are routinely prescribed this new drug therapy. The Roflumilast in the Prevention of COPD Exacerbations While Taking Appropriate Combination Treatment (REACT) study protocol was recently published to address this gap in the literature by evaluating whether the addition of roflumilast to inhaled combination therapy further reduces exacerbations in patients who are having frequent exacerbations despite optimized treatment.
Of additional interest regarding roflumilast therapy, evaluation of specific patient subset responders to this medication verifies the concept that there are different phenotypes of COPD. In the evolving world of personalized medicine, identifying those patient subgroups who respond to PDE4 inhibitors may allow for more targeted therapies in patients with certain phenotypes. Patients with a frequent exacerbator phenotype, defined as > 2 exacerbations per year, benefited from roflumilast therapy independent of long-acting bronchodilator or ICS use. These patients shifted from being frequent exacerbators to more stable infrequent exacerbators, which can be extrapolated to conclude that the anti-inflammatory effects of roflumilast can stabilize the disease in frequent exacerbator phenotypes. The different mechanism of action of this agent compared with current COPD treatment options has the potential to provide additive benefits in the management of COPD.
Adverse effects associated with roflumilast include diarrhea, weight loss, nausea, anxiety/depression, and headache. From clinical trial evaluations of these effects, associated diarrhea, nausea, and headache seem to be transient, but weight loss is maintained throughout roflumilast treatment. Patients should be evaluated for their ability to tolerate weight loss (as much as 2 kg has been reported) as well as underlying neuropsychiatric disorders prior to initiating roflumilast treatment. Of course, study results from the REACT trial will provide more prospective data about the clinical significance of such side effects.