A New Treatment for COPD
Roflumilast With Long Acting Beta2 Agonists for COPD: Influence of Exacerbation History
Bateman ED, Rabe KF, Calverley PM, et al
Eur Respir J. 2011;38:553-560
Study SummaryRoflumilast is a phosphodiesterase 4 (PDE4) inhibitor that was approved in late 2011 with the indication of reducing acute exacerbations in patients with chronic obstructive pulmonary disease (COPD). Two large pivotal trials were performed to obtain approval from the US Food and Drug Administration, each with about 1500 patients; many important and clinically useful outcomes can be found on closer examination of these trials. One question that arose is whether roflumilast would reduce exacerbations in patients who were also receiving a long-acting beta-2 agonist (LABA), as LABAs have also been shown to reduce exacerbation frequency. The data from the pivotal trials were re-examined to address this issue.
Approximately half the patients in the pooled trial received concomitant LABA. In these, the relative risk for exacerbations was 0.79 in those in the roflumilast arms vs 0.85 for those receiving LABA but not roflumilast. The difference was statistically significant (P < .039). The time to first exacerbation was similarly prolonged by roflumilast, particularly in patients who had frequent exacerbations. The conclusion was that roflumilast was effective and reduced the rate of exacerbations even in patients who were receiving a LABA.
ViewpointThis finding is interesting because the patients for whom roflumilast is recommended have severe or very severe COPD and are thus very likely to already be receiving all recommended COPD therapies, including long-acting bronchodilators.[1] The present report reassures clinicians that despite the use of a LABA, roflumilast will still have its intended effect and further reduce the risk for an acute exacerbation.
Acute exacerbations are very serious events in the long-term course of COPD. They are extremely debilitating and can persist for weeks or months. They can also be fatal in 5%-20% of cases. They contribute to a more rapid decline in lung function and quality of life and are also very expensive events, particularly if the patient requires hospitalization. Therefore, a reduction in the frequency and severity of acute exacerbations of COPD is an important goal of therapy, and roflumilast contributes to that goal.
It should also be mentioned that roflumilast represents the first new class of agents for COPD in almost 3 decades. It is a PDE4 inhibitor, the enzyme PDE4 being thought to contribute to both bronchoconstriction and to inflammation in the COPD airways. If so, this would contribute to our need for an anti-inflammatory agent that was active against neutrophilic inflammation -- the type that is present in COPD airways and that is poorly responsive to corticosteroids.
Other features of roflumilast are that it has a small but not clinically meaningful bronchodilator effect, so it should not be used as a bronchodilator. Some patients report that they feel better when they take it, but the majority do not; the motivation for continued use should be the expected reduction in acute exacerbations. The ideal candidates are those with severe or very severe COPD with a bronchitic component, particularly those who have experienced at least 1 previous acute exacerbation.[2]
Adverse events include gastrointestinal disturbance. Nausea and diarrhea occur in 10% to 20% of patients, usually within the first month of treatment, and these symptoms will prevent some patients from taking roflumilast on a long-term basis. Weight loss occurred in 7.5% of patients, again mostly in the first few months of use. Average weight loss was 4-5 lb at the end of 12 months. There are warnings of neuropsychiatric effects such as insomnia, anxiety, depression, and suicidal ideation.
The only contraindication due to concomitant disorder is liver impairment (Child-Pugh B or C). Use by nursing mothers is not recommended. Concomitant use with drugs that enhance the P450 system is not recommended; these are rifampin, carbamazepine, phenytoin, and phenobarbital. Roflumilast is compatible with all drugs commonly used for COPD. There is only 1 dosage strength, 500 mg, and no dose adjustment is required with concomitant medications or renal impairment.[3]
References
Bateman ED, Rabe KF, Calverley PM, et al
Eur Respir J. 2011;38:553-560
Study SummaryRoflumilast is a phosphodiesterase 4 (PDE4) inhibitor that was approved in late 2011 with the indication of reducing acute exacerbations in patients with chronic obstructive pulmonary disease (COPD). Two large pivotal trials were performed to obtain approval from the US Food and Drug Administration, each with about 1500 patients; many important and clinically useful outcomes can be found on closer examination of these trials. One question that arose is whether roflumilast would reduce exacerbations in patients who were also receiving a long-acting beta-2 agonist (LABA), as LABAs have also been shown to reduce exacerbation frequency. The data from the pivotal trials were re-examined to address this issue.
Approximately half the patients in the pooled trial received concomitant LABA. In these, the relative risk for exacerbations was 0.79 in those in the roflumilast arms vs 0.85 for those receiving LABA but not roflumilast. The difference was statistically significant (P < .039). The time to first exacerbation was similarly prolonged by roflumilast, particularly in patients who had frequent exacerbations. The conclusion was that roflumilast was effective and reduced the rate of exacerbations even in patients who were receiving a LABA.
ViewpointThis finding is interesting because the patients for whom roflumilast is recommended have severe or very severe COPD and are thus very likely to already be receiving all recommended COPD therapies, including long-acting bronchodilators.[1] The present report reassures clinicians that despite the use of a LABA, roflumilast will still have its intended effect and further reduce the risk for an acute exacerbation.
Acute exacerbations are very serious events in the long-term course of COPD. They are extremely debilitating and can persist for weeks or months. They can also be fatal in 5%-20% of cases. They contribute to a more rapid decline in lung function and quality of life and are also very expensive events, particularly if the patient requires hospitalization. Therefore, a reduction in the frequency and severity of acute exacerbations of COPD is an important goal of therapy, and roflumilast contributes to that goal.
It should also be mentioned that roflumilast represents the first new class of agents for COPD in almost 3 decades. It is a PDE4 inhibitor, the enzyme PDE4 being thought to contribute to both bronchoconstriction and to inflammation in the COPD airways. If so, this would contribute to our need for an anti-inflammatory agent that was active against neutrophilic inflammation -- the type that is present in COPD airways and that is poorly responsive to corticosteroids.
Other features of roflumilast are that it has a small but not clinically meaningful bronchodilator effect, so it should not be used as a bronchodilator. Some patients report that they feel better when they take it, but the majority do not; the motivation for continued use should be the expected reduction in acute exacerbations. The ideal candidates are those with severe or very severe COPD with a bronchitic component, particularly those who have experienced at least 1 previous acute exacerbation.[2]
Adverse events include gastrointestinal disturbance. Nausea and diarrhea occur in 10% to 20% of patients, usually within the first month of treatment, and these symptoms will prevent some patients from taking roflumilast on a long-term basis. Weight loss occurred in 7.5% of patients, again mostly in the first few months of use. Average weight loss was 4-5 lb at the end of 12 months. There are warnings of neuropsychiatric effects such as insomnia, anxiety, depression, and suicidal ideation.
The only contraindication due to concomitant disorder is liver impairment (Child-Pugh B or C). Use by nursing mothers is not recommended. Concomitant use with drugs that enhance the P450 system is not recommended; these are rifampin, carbamazepine, phenytoin, and phenobarbital. Roflumilast is compatible with all drugs commonly used for COPD. There is only 1 dosage strength, 500 mg, and no dose adjustment is required with concomitant medications or renal impairment.[3]
References
- Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011. http://www.goldcopd.org/ Accessed February 4, 2012.
- Rennard SI, Calverley PM, Goehring UM, Bredenbröker D, Martinez FJ. Reduction of exacerbations by the PDE4 inhibitor roflumilast - the importance of defining different subsets of patients with COPD. Respir Res. 2011;12:18.
- [No authors listed] Roflumilast (Daliresp) for COPD. Med Lett Drugs Ther. 2011;53:59-60. Abstract