Roflumilast - Drug Monograph

Introduction

Roflumilast is an orally administered selective phosphodiesterase-4 (PDE4) inhibitor approved for the treatment of severe chronic obstructive pulmonary disease (COPD). It represents a unique class of medication that targets inflammation rather than providing direct bronchodilation. Roflumilast is indicated specifically to reduce the risk of COPD exacerbations in patients with chronic bronchitis and a history of exacerbations.

Mechanism of Action

Roflumilast works through selective inhibition of phosphodiesterase-4 (PDE4), an enzyme that breaks down cyclic adenosine monophosphate (cAMP). By inhibiting PDE4, roflumilast increases intracellular cAMP levels in lung cells, which leads to:

• Downregulation of inflammatory responses
• Inhibition of neutrophil and eosinophil chemotaxis
• Reduction in production of pro-inflammatory cytokines (TNF-α, IL-8)
• Decreased airway inflammation

This anti-inflammatory mechanism differentiates roflumilast from bronchodilators and corticosteroids in COPD management.

Indications

FDA-approved indications:

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

Not indicated for relief of acute bronchospasm

Dosage and Administration

• 500 mcg orally once daily

• May be taken with or without food
• Tablet should be swallowed whole, not crushed or chewed

• Hepatic impairment: Contraindicated in moderate to severe hepatic impairment (Child-Pugh B or C)
• Renal impairment: No dosage adjustment necessary
• Geriatric patients: No dosage adjustment necessary
• Not recommended in pediatric patients

Pharmacokinetics

• Oral bioavailability: Approximately 80%
• Time to peak concentration (Tmax): 1 hour (roflumilast), 8 hours (active metabolite)
• Food does not significantly affect absorption

• Protein binding: Approximately 99% (roflumilast and active metabolite)
• Volume of distribution: Approximately 2.9 L/kg

• Extensive hepatic metabolism via CYP3A4 and CYP1A2
• Metabolized to its active N-oxide metabolite
• Active metabolite has similar PDE4 inhibitory activity

• Half-life: 17 hours (roflumilast), 30 hours (active metabolite)
• Primarily eliminated via urine (70%) and feces (20%)
• Less than 1% excreted unchanged

Contraindications

1. Moderate to severe hepatic impairment (Child-Pugh B or C) 2. History of hypersensitivity to roflumilast or any component of the formulation

Warnings and Precautions

• Not for relief of acute bronchospasm

• Psychiatric events: May cause insomnia, anxiety, depression, and suicidal ideation
• Weight loss: Significant weight loss observed during treatment; monitor weight regularly
• Drug interactions with strong CYP3A4 inducers or inhibitors
• Not a bronchodilator and should not be used for immediate relief of acute respiratory symptoms

Drug Interactions

• Strong CYP3A4 inhibitors (ketoconazole, ritonavir): May increase roflumilast exposure
• Strong CYP3A4 inducers (rifampin, phenobarbital, carbamazepine): May decrease efficacy
• Oral contraceptives containing gestodene and ethinyl estradiol: May increase exposure to these hormones

Adverse Effects

• Diarrhea (9.5%)
• Weight loss (7.5%)
• Nausea (4.7%)
• Headache (4.4%)
• Insomnia (3.4%)
• Back pain (3.0%)
• Influenza (2.8%)
• Dizziness (2.5%)

• Psychiatric events (depression, suicidal ideation)
• Significant weight loss
• Liver enzyme elevations

Monitoring Parameters

1. Lung function (FEV1) and COPD symptoms 2. Body weight at regular intervals 3. Psychiatric symptoms (mood changes, depression, suicidal thoughts) 4. Liver function tests (baseline and periodically) 5. Signs of infection 6. Efficacy in reducing exacerbation frequency

Patient Education

• Take medication exactly as prescribed, once daily
• This is not a rescue medication and will not relieve sudden breathing problems
• Report any mood changes, depression, or suicidal thoughts immediately
• Monitor your weight regularly and report significant weight loss
• Do not stop taking without consulting your healthcare provider
• Keep all follow-up appointments
• Inform all healthcare providers about all medications you're taking
• Store at room temperature away from moisture and heat

References

1. FDA Prescribing Information: Daliresp (roflumilast) tablets 2. Calverley PMA, Rabe KF, Goehring U-M, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374(9691):685-694. 3. Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br J Pharmacol. 2011;163(1):53-67. 4. Global Initiative for Chronic Obstructive Lung Disease. 2023 Report. 5. Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet. 2009;374(9691):695-703.