ROFLUMILAST
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ROFLUMILAST (ROFLUMILAST).
Selective phosphodiesterase 4 (PDE4) inhibitor; increases intracellular cyclic AMP levels, reducing inflammation and relaxing smooth muscle in the airways.
| Metabolism | Primarily hepatic via CYP1A2 and CYP3A4; also metabolized by conjugative pathways (glucuronidation). |
| Excretion | Primarily hepatic metabolism via CYP3A4 and CYP1A2, with metabolites excreted in urine (40-50% as metabolites) and feces (40-50% as metabolites). Less than 1% excreted unchanged. |
| Half-life | Terminal elimination half-life approximately 29-30 hours in COPD patients, allowing once-daily dosing. Steady-state reached in 4-5 days. |
| Protein binding | Approximately 99% bound, primarily to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | 2.9-3.4 L/kg, indicating extensive tissue distribution beyond plasma volume. |
| Bioavailability | Oral bioavailability approximately 80%. |
| Onset of Action | Oral: Clinical improvement in lung function (FEV1) observed within 4-8 weeks; maximum benefit may require 6 months of continuous therapy. |
| Duration of Action | Sustained bronchodilation with once-daily dosing; effects persist for 24 hours. Clinical improvement maintained with continuous use; discontinuation leads to loss of benefit over several weeks. |
500 mcg orally once daily.
| Dosage form | TABLET |
| Renal impairment | No dosage adjustment required for GFR ≥30 mL/min. Insufficient data for GFR <30 mL/min; use with caution. |
| Liver impairment | Contraindicated in Child-Pugh class B or C. No adjustment needed for Child-Pugh class A. |
| Pediatric use | Not approved. Safety and efficacy not established in pediatric patients. |
| Geriatric use | No specific dosage adjustment recommended; monitor for tolerability and adverse events due to potential comorbidities and polypharmacy. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ROFLUMILAST (ROFLUMILAST).
| Breastfeeding | No data on presence in human breast milk; animal studies indicate excretion in milk. M/P ratio: unknown. Due to potential for serious adverse reactions in nursing infants, breastfeeding is not recommended during roflumilast therapy. |
| Teratogenic Risk | Roflumilast is contraindicated in pregnancy (FDA Pregnancy Category C, but due to lack of adequate studies and potential fetal harm, it should not be used). Animal studies show embryofetal toxicity including reduced fetal weights, skeletal variations, and increased post-implantation loss at clinically relevant doses. Trimester-specific risks: First trimester: potential teratogenic effects (anomalies observed in animals); Second/Third trimesters: risk of fetal toxicity (low birth weight, developmental delay). |
■ FDA Black Box Warning
None.
| Serious Effects |
["Moderate to severe hepatic impairment (Child-Pugh B or C)","History of hypersensitivity to roflumilast or any component of the formulation"]
| Precautions | ["Psychiatric events: increased risk of suicidality, depression, anxiety; monitor mood and behavior","Weight loss: monitor weight regularly; avoid in patients with unexplained significant weight loss","Hepatic impairment: not recommended in severe hepatic impairment (Child-Pugh B or C)","Drug interactions: avoid strong CYP1A2 inhibitors (e.g., ciprofloxacin, fluvoxamine) and strong CYP3A4 inhibitors (e.g., ketoconazole)"] |
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| Fetal Monitoring | Pregnancy test before initiation (if applicable); fetal ultrasound monitoring if exposure occurs; maternal weight, psychiatric status (suicidality risk), and gastrointestinal symptoms monitoring. |
| Fertility Effects | In animal studies, no effect on male or female fertility at exposures up to 8 times the human therapeutic dose. However, as a PDE4 inhibitor, theoretical risk of hormonal disruption; clinical data insufficient in humans. |