Roflumilast

• Chronic Obstructive Pulmonary Disease
• Chronic Bronchitis
• COPD Exacerbation Prevention

Roflumilast is a selective phosphodiesterase-4 (PDE4) inhibitor used as add-on maintenance therapy for severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis and a history of frequent exacerbations. It works by reducing inflammation in the lungs through a unique oral mechanism distinct from inhaled therapies.

Mechanism of Action

Roflumilast exerts its therapeutic effects through selective enzyme inhibition:

• PDE4 inhibition: Blocks phosphodiesterase-4, the major phosphodiesterase in inflammatory cells
• Increases intracellular cAMP: Elevates cyclic adenosine monophosphate levels in lung cells
• Anti-inflammatory effects: Reduces release of inflammatory mediators from neutrophils, eosinophils, monocytes, and macrophages
• Decreases airway inflammation: Reduces inflammatory cell counts in sputum

The active metabolite, roflumilast N-oxide, contributes approximately 90% of the total PDE4 inhibitory activity and has a longer half-life than the parent compound.

Available Formulations

Roflumilast is available as oral tablets:

• 500 mcg (0.5 mg) tablets (Daliresp)
• 250 mcg tablets (for titration in some regions)

Medical Uses

FDA-Approved Indication:

• Maintenance treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations

Roflumilast is used as add-on therapy to bronchodilators and is not a bronchodilator itself. It does not provide immediate relief of bronchospasm.

Dosing Guidelines

Adults:

• 500 mcg once daily orally
• Take with or without food
• Some regions recommend starting with 250 mcg for 4 weeks to improve tolerability

Important Considerations:

• Effects on lung function may take weeks to months to become apparent
• Continue even during exacerbation-free periods
• Not for acute bronchospasm relief

Important Safety Information

Contraindications:

• Moderate to severe hepatic impairment (Child-Pugh B or C)

Warnings and Precautions:

• Psychiatric events: May cause depression, suicidal ideation, and behavior; weigh risks vs benefits in patients with history of depression or suicidal thoughts
• Weight loss: Monitor weight regularly; unexplained or significant weight loss may require discontinuation
• Drug interactions: CYP3A4/CYP1A2 inducers and inhibitors may affect exposure
• Not a bronchodilator: Do not use for acute bronchospasm

Drug Interactions

• CYP3A4/CYP1A2 inhibitors (erythromycin, ketoconazole, fluvoxamine, cimetidine): Increase roflumilast exposure; use with caution
• CYP3A4/CYP1A2 inducers (rifampicin, phenobarbital, carbamazepine, phenytoin): Decrease roflumilast efficacy; avoid concurrent use
• Oral contraceptives (gestodene, ethinyl estradiol): May increase roflumilast exposure
• Theophylline: No significant interaction; can be used together
• Immunosuppressants: Limited data; use with caution

Special Populations

• Hepatic Impairment: Contraindicated in moderate to severe impairment (Child-Pugh B or C); use with caution in mild impairment
• Renal Impairment: No dose adjustment required
• Elderly: No dose adjustment needed; monitor for psychiatric symptoms
• Pregnancy: Category C; use only if benefit outweighs risk
• Lactation: Not recommended during breastfeeding
• Pediatric: Safety and efficacy not established