Roflumilast was approved by the Food and Drug Administration March 1 to decrease the frequency of exacerbations in patients with severe chronic obstructive pulmonary disease associated with chronic bronchitis and a history of exacerbations.
The drug is the only PD-4 inhibitor approved for this indication, according to Forest Pharmaceuticals, which developed the agent. It will be marketed as Daliresp and is expected to be commercially available later this year.
Roflumilast will be available in 500-mcg pills to be taken daily for the prevention of COPD flares in patients with severe disease, according to the agency.
The decision stands in contrast to an FDA advisory panel’s recommendation. In April 2010, members of the Pulmonary-Allergy Drugs Advisory Committee voted 10-5 that the efficacy and safety data on the drug did not support approval for the maintenance treatment of COPD associated with chronic bronchitis in patients at risk of exacerbations.
This was the original proposed indication, but in January 2010 – a month after Forest Research Institute Inc., acquired the drug from another company – Forest changed the proposed indication to a more focused one: "Maintenance treatment to reduce exacerbations of COPD." Because this was done 6 months into the FDA review period, however, the panel was asked to vote on the original indication.
The reasons panelists gave for voting against approval of the original, broader indication included what some described as the "meager" or modest beneficial effect of roflumilast in studies, the need to compare it with other COPD treatments like theophylline (a nonspecific PDE inhibitor and the only PDE inhibitor marketed in the United States), and the need to evaluate its efficacy when added to standard COPD treatments like inhaled corticosteroids.
Its efficacy and safety were evaluated in eight clinical studies comprising 9,394 adult patients, of whom 4,425 took the drug, according a statement issued by Forest. Two of these studies were 1-year placebo-controlled trials that together enrolled more than 3,100 patients. Those treated had a history of COPD associated with chronic bronchitis and had experienced an exacerbation of the disease during the 12 months before beginning treatment. All patients were taking concomitant medications, including long- and short-acting beta-2 agonists or short-acting anticholinergics.
Overall, the drug reduced the rate of moderate or severe exacerbations by 15% in one trial and 18% in the other, compared with placebo. The drug also improved prebronchodilator lung function.
Among the eight trials, most common adverse reactions in those taking the drug included diarrhea, weight decrease, nausea, headache, back pain, influenza, insomnia, dizziness, and decreased appetite. Fourteen percent of patients taking roflumilast withdrew from the studies because of adverse events: 5% for gastrointestinal upset and the rest for other problems. Serious adverse events occurred in 14% of those taking placebo and 13% of those taking roflumilast. Death from COPD occurred in 20 patients in the roflumilast group and 22 in the placebo group – not a significant difference.
The company also noted that weight change occurred more often in those taking the drug. It occurred mostly in obese rather than underweight patients and caused no increased morbidity relative to placebo. However, the company warned in a 2010 FDA presentation, "patients and physicians should be informed that weight loss is associated with roflumilast and weight should be regularly monitored."
The drug is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C), according to the company’s statement.
Other safety warnings will appear on the packaging:
• Roflumilast is not a bronchodilator and should not be used for the relief of acute bronchospasm.
• Psychiatric events including suicidality are associated with its use, occurring in 5.9% of treated patients compared with 3.3% of those taking placebo. Three patients experienced suicide-related adverse reactions, with one completion and two attempts, compared with one suicidal ideation in one placebo-treated patient.
• The drug should not be used in conjunction with strong P450 enzyme inducers and used with caution in patients taking inhibitors of the CYP3A4 or CYP1A2 enzymes.
• Roflumilast should not be used by pregnant women unless the risks and benefits are carefully weighed, and should not be taken during labor and delivery.
The drug’s mechanism of action is not fully understood, the company noted. "It is thought to be related to the effects of increased intracellular adenosine monophosphate."