PIRFENIDONE
Clinical safety rating
cautionComprehensive clinical and safety monograph for PIRFENIDONE (PIRFENIDONE).
Pirfenidone is a pyridone derivative that inhibits TGF-β1-mediated collagen synthesis, reduces fibroblast proliferation, and downregulates the production of pro-inflammatory cytokines (e.g., TNF-α, IL-1β) and growth factors. Its exact mechanism in idiopathic pulmonary fibrosis (IPF) is not fully elucidated, but it is thought to exert antifibrotic and anti-inflammatory effects.
| Metabolism | Primarily hepatic metabolism via CYP1A2, with minor contributions from other CYP enzymes (CYP2C9, CYP2C19, CYP2D6, CYP2E1). |
| Excretion | Renal: ~80% (mostly as unchanged drug and metabolites); fecal: ~20%. |
| Half-life | Terminal elimination half-life: ~2.5 hours (range 1.5–3.5 h); clinical context: no accumulation with twice-daily dosing; steady-state reached within 2–3 days. |
| Protein binding | ~60–70% bound to plasma proteins (primarily albumin). |
| Volume of Distribution | Vd: ~1 L/kg (range 0.8–1.2 L/kg); clinical meaning: extensive tissue distribution. |
| Bioavailability | Oral: ~80–85% (high bioavailability with minimal first-pass metabolism). |
| Onset of Action | Oral: clinical antifibrotic effects observed after months of therapy; no acute onset. |
| Duration of Action | Duration: not applicable for acute effect; continuous therapy required for sustained benefit; maximum effect on decline in forced vital capacity (FVC) seen over 52–72 weeks in clinical trials. |
| Molecular Weight | 185.22 |
801 mg orally three times daily with food, total daily dose 2403 mg. Starting dose: 267 mg three times daily for first 7 days, then 534 mg three times daily for 7 days, then maintenance 801 mg three times daily.
| Dosage form | TABLET |
| Renal impairment | Contraindicated in GFR < 30 mL/min. For GFR 30-50 mL/min: reduce to 267 mg three times daily; monitor for adverse effects. No adjustment for GFR > 50 mL/min. |
| Liver impairment | Child-Pugh Class A: no adjustment. Child-Pugh Class B: contraindicated (insufficient data). Child-Pugh Class C: contraindicated. |
| Pediatric use | Not approved for pediatric patients; safety and efficacy not established. No weight-based dosing guidelines available. |
| Geriatric use | No specific dose adjustment required; use caution due to potential increased sensitivity and higher incidence of renal impairment. Monitor renal function and gastrointestinal tolerability. |
| 1st trimester | Avoid: limited human data; animal studies show fetal harm (skeletal abnormalities, decreased fetal weight). |
| 2nd trimester | Avoid: potential fetal risk; use only if benefit outweighs risk. |
| 3rd trimester | Avoid: potential fetal risk; may cause oligohydramnios due to renal effects. |
Clinical note
Comprehensive clinical and safety monograph for PIRFENIDONE (PIRFENIDONE).
| Placental transfer | Expected to cross placenta based on low molecular weight and animal studies showing placental transfer. |
| Breastfeeding | Not recommended; no human data on excretion in milk; due to potential adverse reactions in infant, discontinue drug or nursing. |
| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | Pirfenidone is classified as FDA Pregnancy Category C. In animal studies, it caused fetal toxicity (reduced fetal weight, increased skeletal variations) at doses below human exposure. There are no adequate and well-controlled studies in pregnant women. The risk of major birth defects is unknown; use only if potential benefit justifies potential risk to the fetus. First trimester: potential for teratogenicity. Second and third trimester: possible fetal toxicity from maternal exposure. |
| Fetal Monitoring | Monitor liver function tests (ALT, AST, bilirubin) monthly. Assess renal function (serum creatinine, BUN) periodically. Monitor for gastrointestinal effects (nausea, dyspepsia) and photosensitivity. For pregnant patients, consider serial fetal growth ultrasound due to potential for low birth weight. |
| Fertility Effects | In animal studies, pirfenidone affected fertility (reduced pregnancy rates, increased pre-implantation loss) at doses lower than human therapeutic exposure. Human data are lacking; advise patients of potential reversible fertility impairment. |
■ FDA Black Box Warning
No FDA black box warnings.
| Serious Effects |
Hypersensitivity to pirfenidone or any excipientSevere hepatic impairmentSevere renal impairment (CrCl < 30 mL/min)Concomitant use with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin)
| Precautions | Hepatotoxicity: Elevations in liver enzymes and potential drug-induced liver injury; monitor LFTs regularly., Photosensitivity: Avoid sun exposure; use broad-spectrum sunscreen., Gastrointestinal effects: Nausea, diarrhea, dyspepsia; may require dose adjustment., Drug interactions: Coadministration with strong CYP1A2 inhibitors (e.g., fluvoxamine) increases pirfenidone exposure; use with caution., Smoking: Tobacco smoking induces CYP1A2, reducing pirfenidone exposure; advise smoking cessation. |
| Food/Dietary | Avoid grapefruit juice (CYP3A4 interaction). Take with food to minimize GI upset. No other significant food interactions. |
| Clinical Pearls | Monitor liver function tests monthly for first 6 months, then every 3 months. Avoid use in moderate to severe hepatic impairment (Child-Pugh B/C). Photosensitivity is common; advise sun avoidance and broad-spectrum sunscreen. May cause gastrointestinal issues; take with food. Dose reduction required with strong CYP1A2 inhibitors (e.g., fluvoxamine). Smoking induces CYP1A2 and reduces exposure. |
| Patient Advice | Take with food to reduce stomach upset. · Avoid sun exposure; use sunscreen and protective clothing. · Report any signs of liver problems: jaundice, dark urine, abdominal pain. · Do not smoke while taking this medication. · Avoid grapefruit juice. · Complete blood tests as scheduled. |
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