Roflumilast
Roflumilast
Generic Name
Roflumilast
Mechanism
- Selective PDE4 inhibition → ↑ intracellular cyclic‑adenosine monophosphate (cAMP).
- ↑cAMP ↓ intracellular calcium, suppressing the release of pro‑inflammatory mediators (TNF‑α, IL‑8, MMP‑9).
- Leads to anti‑inflammatory effects in airway epithelium and neutrophils.
- Modulates mast‑cell degranulation and reduces mucus hypersecretion.
Pharmacokinetics
| Parameter | Detail |
| Route | Oral capsule |
| Absorption | Rapid, T_max 0.5–3 h |
| Bioavailability | ~50% (first‑pass hepatic metabolism) |
| Metabolism | CYP3A4‑mediated oxidation → 3‑hydroxy metabolite (active) |
| Elimination | ~90% fecal (biliary), 10% renal (urea, creatinine) |
| Half‑life | 12 h (steady‑state ~1 day) |
| Protein binding | > 95% |
| Drug interactions | Potentiated by strong CYP3A4 inhibitors (ketoconazole, clarithromycin) → ↑ toxicity; increased with strong CYP3A4 inducers (rifampin, carbamazepine) → ↓ efficacy |
Indications
- COPD with chronic bronchitis & at least 2 moderate or 1 severe exacerbation in the past 12 months despite LABA/LAMA ± inhaled corticosteroid.
- Add‑on therapy to inhaled bronchodilators; not a bronchodilator itself.
> *Off‑label*: asthma with steroid‑refractory exacerbations (data limited).
Contraindications
- Contraindicated: hypersensitivity to roflumilast or any excipients; severe hepatic impairment (Child‑Pugh class C).
- Warnings:
- Elevated hepatic enzymes → can progress to hepatotoxicity.
- Significant weight loss, nausea, diarrhea.
- Psychiatric adverse effects: anxiety, agitation, depression, insomnia; suicidality risk.
- Use caution in patients with heart failure, severe renal impairment, or concurrent systemic steroids.
Dosing
- Adult dose: 250 µg orally once daily (capsule).
- Hepatic impairment: 125 µg once daily in Child‑Pugh class B.
- Timing: May be taken with or without food.
- Titration: No step‑down; maintain for minimum 4–6 weeks before reassessing benefit.
Adverse Effects
| Category | Frequency |
| GI | Diarrhea, nausea, abdominal pain (≤15%) |
| Weight | Loss ≥5 % body weight (≤10%) |
| Neurologic | Headache, dizziness, insomnia (≤10%) |
| Psychiatric | Mood disturbances, anxiety, depression; rare suicidality (≤0.5%) |
| Hepatic | Elevated ALT/AST (≤5%) |
| Others | Nasopharyngitis, pyrexia (≤5%) |
Monitoring
- Baseline & every 3 months: ALT, AST, total bilirubin.
- Weight: baseline, 3 months, then 6 months.
- Psychiatric screening: baseline, 1 month, 3 months, then annually.
- Renal function: baseline, often repeated if clinically indicated.
- Exacerbation frequency: track to evaluate clinical benefit.
Clinical Pearls
- Target population: COPD patients with repeated exacerbations *on* LABA/LAMA ± inhaled steroid; add‑on therapy only.
- Adjuvant therapy: Does not replace inhaled corticosteroids—use in addition, but a *switch from high‑dose inhaled steroids* to roflumilast *is not advised* unless clear clinical benefit.
- Weight loss: Monitor; if >5 % loss, consider dose reduction or discontinuation.
- Psychiatric vigilance: Use a simple patient questionnaire or clinical interview at each visit; particularly crucial in patients with prior mood disorders or taking serotonergic agents.
- Drug interactions: Counsel patients on the importance of notifying prescribers of any new prescription, especially strong CYP3A4 inhibitors/inducers.
- Special populations: Approved (approved dose) for adults >40 kg but *not* recommended for patients <40 kg or children.
- Delivery: Oral capsule; no inhaler formulation—important for patients who may misinterpret as a bronchodilator.
- Therapeutic window: Benefit is modest (≈20% reduction in exacerbation rate); realistic expectations should be set.
- Patient education: Inform on GI side effects, potential mood changes, importance of liver test adherence, and what to do if mood symptoms emerge.
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• Key terms: *Roflumilast*, PDE4 inhibitor, COPD exacerbation prevention, oral therapy, hepatic monitoring.