Usage
- Roflumilast is prescribed for the maintenance treatment of severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis in adult patients with a history of frequent exacerbations. It is used as an add-on to bronchodilator treatment. It is specifically indicated for patients with severe COPD (FEV1 post-bronchodilator less than 50% predicted).
- Pharmacological Classification: Phosphodiesterase-4 (PDE4) inhibitor.
- Mechanism of Action: Roflumilast inhibits PDE4, an enzyme that breaks down cyclic adenosine monophosphate (cAMP). By inhibiting PDE4, roflumilast increases intracellular cAMP levels, leading to a reduction in airway inflammation and smooth muscle relaxation.
Alternate Names
- The International Nonproprietary Name (INN) is roflumilast.
- Brand Names: Daliresp, Daxas.
How It Works
- Pharmacodynamics: Roflumilast’s primary effect is to reduce inflammation in the airways. This leads to decreased mucus production and improved lung function in COPD patients.
- Pharmacokinetics:
- Absorption: Roflumilast is absorbed orally, reaching peak plasma concentrations in approximately 1 hour. Food does not significantly affect absorption.
- Metabolism: Primarily metabolized in the liver by CYP3A4 and CYP1A2 enzymes to its active metabolite, roflumilast N-oxide.
- Elimination: Excreted primarily in the urine (approximately 70%) as inactive metabolites, with the remainder eliminated in the feces. The elimination half-life of roflumilast is approximately 17 hours, and for its N-oxide metabolite, it is about 30 hours.
- Mode of Action: Roflumilast selectively inhibits PDE4, specifically the PDE4B subtype expressed in inflammatory cells, airway smooth muscle, and pulmonary vasculature.
- Receptor Binding/Enzyme Inhibition: Roflumilast acts by binding to the catalytic site of PDE4, inhibiting its enzymatic activity. This increases intracellular cAMP levels which leads to a range of anti-inflammatory and bronchodilatory effects.
- Elimination Pathways: Roflumilast is primarily eliminated by hepatic metabolism and renal excretion of metabolites.
Dosage
Standard Dosage
Adults:
- Starting Dose: 250 mcg orally once daily for 4 weeks.
- Maintenance Dose: 500 mcg orally once daily. The 250 mcg dose is sub-therapeutic and is intended only to reduce the initial side effects.
Children:
- The safety and efficacy of roflumilast have not been established in children under 18 years of age.
Special Cases:
- Elderly Patients: No dose adjustment is necessary.
- Patients with Renal Impairment: No dose adjustment is necessary.
- Patients with Hepatic Dysfunction: Contraindicated in moderate to severe hepatic impairment (Child-Pugh B or C). Use with caution in mild hepatic impairment (Child-Pugh A).
- Patients with Comorbid Conditions: Use cautiously with inhibitors of CYP3A4 and dual inhibitors of CYP3A4 and CYP1A2 (e.g., erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine) or oral contraceptives containing gestodene and ethinyl estradiol as they may increase roflumilast systemic exposure.
Clinical Use Cases
Roflumilast is not indicated for:
- Intubation
- Surgical Procedures
- Mechanical Ventilation
- Intensive Care Unit (ICU) Use
- Emergency Situations (e.g., status epilepticus, cardiac arrest)
Roflumilast is indicated only for the maintenance treatment of severe COPD and should not be used for acute exacerbations. It is not a bronchodilator.
Dosage Adjustments
Dose adjustments may be necessary in patients with hepatic impairment or those taking concomitant medications that affect CYP3A4 or CYP1A2 activity (see Drug Interactions).
Side Effects
Common Side Effects
- Diarrhea
- Weight loss
- Nausea
- Headache
- Back pain
- Insomnia
- Dizziness
- Decreased appetite
- Flu-like symptoms
Rare but Serious Side Effects
- Psychiatric events including anxiety, depression, insomnia, suicidal thoughts, and mood changes
- Hypersensitivity reactions (e.g., skin rash, itching, hives, swelling)
Long-Term Effects
While the drug has been studied in clinical trials for up to one year, the potential long-term effects beyond this period are not fully characterized.
Adverse Drug Reactions (ADR)
Serious ADRs include severe psychiatric events, including suicidality, and hypersensitivity reactions.
Contraindications
- Moderate to severe hepatic impairment (Child-Pugh B or C)
- Hypersensitivity to roflumilast or any of its excipients
Drug Interactions
Roflumilast interacts with several medications, including:
- CYP3A4 Inhibitors: (e.g., erythromycin, ketoconazole, fluvoxamine) can increase roflumilast exposure.
- CYP3A4 and CYP1A2 Dual Inhibitors: (e.g., enoxacin, cimetidine) can also increase roflumilast exposure.
- CYP3A4 Inducers: (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) can decrease roflumilast exposure.
- Oral Contraceptives: containing gestodene and ethinyl estradiol can increase roflumilast exposure.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: C (FDA classification). Roflumilast is not recommended during pregnancy. Animal studies have shown reproductive toxicity at high doses.
- Breastfeeding: Roflumilast is likely excreted in breast milk and may have potential effects on the neonate. Breastfeeding is not recommended while taking roflumilast.
Drug Profile Summary
- Mechanism of Action: PDE4 inhibitor, increases intracellular cAMP, reduces airway inflammation.
- Side Effects: Diarrhea, weight loss, nausea, headache, back pain, insomnia, psychiatric events.
- Contraindications: Moderate/severe hepatic impairment, hypersensitivity.
- Drug Interactions: CYP3A4 inhibitors/inducers, CYP1A2 inhibitors, certain oral contraceptives.
- Pregnancy & Breastfeeding: Not recommended.
- Dosage: Adults: 250 mcg daily for 4 weeks, then 500 mcg daily. Children: Not established.
- Monitoring Parameters: Monitor for psychiatric symptoms, weight, and COPD exacerbations.
Popular Combinations
Roflumilast is typically used in combination with long-acting bronchodilators (LABAs) and inhaled corticosteroids (ICS) in the management of COPD.
Precautions
- General Precautions: Screen for hepatic impairment and psychiatric history before initiating treatment.
- Specific Populations: See Dosage - Special Cases.
- Lifestyle Considerations: Roflumilast has no or negligible influence on the ability to drive or use machines. Advise patients on the potential for side effects such as dizziness that could impact these activities.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Roflumilast?
A: The starting dose is 250 mcg once daily for 4 weeks, followed by a maintenance dose of 500 mcg once daily.
Q2: Is Roflumilast a bronchodilator?
A: No, roflumilast is not a bronchodilator and should not be used to treat acute bronchospasm. It is an anti-inflammatory medication.
Q3: Can Roflumilast be used in patients with liver problems?
A: Roflumilast is contraindicated in patients with moderate to severe hepatic impairment. Use with caution in patients with mild hepatic impairment.
Q4: What are the most common side effects of Roflumilast?
A: The most common side effects include diarrhea, weight loss, nausea, headache, back pain, insomnia, and dizziness.
Q5: Can Roflumilast be used during pregnancy or breastfeeding?
A: Roflumilast is not recommended for use during pregnancy or breastfeeding.
Q6: What should I monitor in patients taking Roflumilast?
A: Monitor patients for psychiatric symptoms (including suicidal ideation), weight loss, and the frequency of COPD exacerbations.
Q7: How long does it take for Roflumilast to become effective?
A: It may take several weeks for patients to experience the full benefit of roflumilast.
Q8: Does Roflumilast interact with other medications?
A: Yes, roflumilast can interact with several medications, including certain antibiotics, antifungals, and other drugs metabolized by the liver. Consult the Drug Interactions section for more information.
Q9: Should the dose of Roflumilast be adjusted for elderly patients?
A: No, dosage adjustment is not typically necessary for elderly patients.
