What is Roflumilast (phosphodiesterase-4 inhibitor)?

What is Roflumilast?

Roflumilast is an oral, once-daily selective phosphodiesterase-4 (PDE4) inhibitor approved to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. 1

Mechanism of Action

Roflumilast and its active metabolite (roflumilast N-oxide) selectively inhibit PDE4, the major cyclic AMP-metabolizing enzyme in lung tissue. 1 This inhibition leads to accumulation of intracellular cyclic AMP, which is thought to reduce lung inflammation, though the precise therapeutic mechanism in COPD remains incompletely defined. 1

In COPD patients, roflumilast reduces sputum neutrophils by 31% and eosinophils by 42% after 4 weeks of treatment. 1 In healthy volunteers challenged with lipopolysaccharide, roflumilast reduced bronchoalveolar lavage neutrophils by 38% and eosinophils by 73%. 1

Clinical Indications and Patient Selection

Roflumilast should be prescribed for patients with severe or very severe airflow obstruction (post-bronchodilator FEV₁/FVC <0.70 and FEV₁ <50% predicted), symptoms of chronic bronchitis, and exacerbations despite optimal inhaled therapy. 2

The ERS/ATS guidelines provide a conditional recommendation for roflumilast in this specific population, emphasizing that patients must have failed optimal inhaled therapy first. 2 The GOLD 2017 strategy document similarly states that roflumilast reduces moderate and severe exacerbations in patients with chronic bronchitis, severe to very severe COPD, and a history of exacerbations. 2

The FDA label specifies that roflumilast is indicated for severe COPD associated with chronic bronchitis and a history of exacerbations, with the important limitation that it is not a bronchodilator and should not be used for acute bronchospasm relief. 1

Clinical Efficacy

Exacerbation Reduction

Roflumilast demonstrates moderate but consistent benefits in reducing COPD exacerbations:

• Reduces moderate or severe exacerbations per patient-year by 15% (rate ratio 0.85,95% CI 0.78-0.91). 2
• Decreases the proportion of patients experiencing exacerbations by 15% (21.4% vs 25.2%; risk ratio 0.85,95% CI 0.78-0.94). 2
• Prolongs time to next exacerbation (hazard ratio 0.88,95% CI 0.81-0.96). 2, 3
• Particularly effective for severe exacerbations requiring hospitalization (rate ratio 0.76,95% CI 0.60-0.95 in the largest trial). 2

The ACCP/CTS guidelines found that roflumilast reduced the mean rate of exacerbations per year with a hazard ratio of 0.85 (95% CI 0.79-0.92). 2

Lung Function Improvements

Roflumilast produces modest but statistically significant improvements in lung function:

• Increases post-bronchodilator FEV₁ by 56 mL (95% CI 45-67 mL). 2
• Increases FVC by 98 mL (95% CI 79-118 mL). 2

Use with Concomitant Bronchodilators

Roflumilast remains effective when added to long-acting bronchodilators. 2 It reduces exacerbations both with LABA (rate ratio 0.79,95% CI 0.69-0.91) and without LABA (rate ratio 0.85,95% CI 0.74-0.99). 4 The drug can be used concomitantly with all forms of bronchodilators without increasing adverse events. 4

Adverse Effects and Safety Profile

Roflumilast has significant gastrointestinal, psychiatric, and weight-related adverse effects that lead to treatment discontinuation in approximately 15% of patients. 2

Common Adverse Effects (compared to placebo):

• Diarrhea: 9.7% vs 2.7% (risk ratio 3.96,95% CI 3.20-4.89) 2
• Nausea: 4.8% vs 1.4% (risk ratio 3.54,95% CI 2.63-4.78) 2
• Weight loss: 8.4% vs 2.3% (risk ratio 3.94,95% CI 3.11-5.00), averaging 2.2 kg 2, 5
• Psychiatric disorders (anxiety, depression): 7.1% vs 3.5% (risk ratio 2.13,95% CI 1.79-2.54) 2
• Sleep disturbance/insomnia: 3.1% vs 1.1% (risk ratio 2.88,95% CI 2.15-3.86) 2
• Headache is also commonly reported 5

Treatment Discontinuation

Premature discontinuation due to adverse effects occurs more frequently with roflumilast than placebo (14.9% vs 9.0%; risk ratio 1.80,95% CI 1.58-2.04). 2 Most discontinuations occur during the first few weeks of therapy and are typically related to gastrointestinal side effects. 5

Mortality and Cardiovascular Safety

Roflumilast has no effect on mortality (2.4% vs 2.4%; risk ratio 0.99,95% CI 0.70-1.42) or cardiovascular events (5.4% vs 4.9%; risk ratio 1.11,95% CI 0.88-1.40). 2

Dosing and Administration

The FDA-approved dosing regimen starts with 250 mcg once daily for the first 4 weeks, then increases to the therapeutic dose of 500 mcg once daily. 1 The 250 mcg dose is a starting dose only and is not therapeutically effective. 1

Roflumilast is administered as an oral tablet once daily, which offers a convenience advantage over inhaler therapy. 5 Food delays time to maximum concentration by one hour and reduces peak concentration by 40%, but does not affect total drug absorption. 1

Contraindications and Precautions

Hepatic Impairment

Roflumilast is contraindicated in patients with moderate or severe liver impairment (Child-Pugh B or C). 1 In Child-Pugh B patients, AUC increases by 92% for roflumilast and 41% for the active metabolite. 1 Clinicians should carefully consider the risk-benefit ratio in patients with mild hepatic impairment (Child-Pugh A). 1

Special Populations

• Underweight patients: Roflumilast should be avoided due to the risk of further weight loss. 2
• Depression: Use with caution in patients with depression given the increased risk of psychiatric adverse effects. 2
• Renal impairment: No dosage adjustment is necessary. 1
• Geriatric patients: No dosage adjustment is required based on age alone. 1

Important Clinical Limitations

Roflumilast is not a bronchodilator and must not be used for acute symptom relief or bronchospasm. 1 It should only be considered as add-on therapy after patients have failed optimal inhaled therapy, including long-acting bronchodilators and inhaled corticosteroids where appropriate. 2

The evidence base for roflumilast is predominantly derived from patients with severe or very severe airflow obstruction; its efficacy in patients with mild or moderate COPD remains unknown and represents an important research gap. 2

Clinical Context and Positioning

The ERS/ATS recommendation places high value on preventing exacerbations and lower value on the burden, cost, and adverse effects of daily medication. 2 This reflects the reality that while roflumilast provides meaningful exacerbation reduction, particularly for severe exacerbations requiring hospitalization, the adverse effect profile limits its tolerability in clinical practice. 2

Roflumilast represents the first oral PDE4 inhibitor approved for COPD and offers an alternative mechanism of action to inhaled therapies, targeting the inflammatory processes underlying COPD. 5, 6 However, its role remains as adjunctive therapy in a specific phenotype of COPD patients who continue to exacerbate despite optimal inhaled treatment. 2, 7