Esbriet (Pirfenidone)
pirfenidone — pyridone anti-fibrotic agent
Indications
Pirfenidone was the first anti-fibrotic oral therapy approved for IPF, gaining FDA approval in October 2014 under the breakthrough therapy designation. It belongs to the pyridone chemical class and exerts anti-fibrotic, anti-inflammatory, and antioxidant effects, although its precise mechanism of action remains incompletely defined. Pirfenidone reduces the rate of lung function decline in IPF and is one of only two approved anti-fibrotic agents alongside nintedanib.
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Idiopathic pulmonary fibrosis (IPF) | Adults | Monotherapy | FDA Approved |
Unlike nintedanib, pirfenidone is currently approved only for IPF and does not have FDA indications for progressive fibrosing ILDs (PPF) or SSc-ILD. However, pirfenidone can be combined with nintedanib without pharmacokinetic interaction, and several trials have explored its use in non-IPF fibrosing ILDs.
Progressive fibrosing ILDs (non-IPF) — The RELIEF trial evaluated pirfenidone in progressive fibrosing ILDs other than IPF and showed a reduced rate of FVC decline. However, the trial was terminated early due to slow enrollment. Evidence quality: moderate.
Unclassifiable progressive ILD — Limited data from retrospective series and the RELIEF trial. Evidence quality: low.
Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| IPF — initial titration (Days 1–7) | 267 mg TID with food | 801 mg/day | 2403 mg/day | Week 1 of 2-week titration Titration reduces early GI and photosensitivity events |
| IPF — titration (Days 8–14) | 534 mg TID with food | 1602 mg/day | 2403 mg/day | Week 2 of titration Two 267 mg capsules or two 267 mg tablets per dose |
| IPF — full maintenance (Day 15 onward) | 801 mg TID with food | 2403 mg/day | 2403 mg/day | Three 267 mg capsules/tablets OR one 801 mg tablet per dose 801 mg tablet reduces pill burden from 9 to 3 per day |
| With strong CYP1A2 inhibitor (fluvoxamine, enoxacin) | 267 mg TID | 801 mg/day | 801 mg/day | Reduce to one-third of full dose Fluvoxamine increases exposure ~4-fold (nonsmokers), ~7-fold (smokers) |
| With moderate CYP1A2 inhibitor (ciprofloxacin 750 mg BID) | 534 mg TID | 1602 mg/day | 1602 mg/day | Reduce to two-thirds of full dose Ciprofloxacin 750 mg BID increases pirfenidone exposure by ~81% |
If pirfenidone is interrupted for 14 or more consecutive days, the full 2-week titration must be repeated. For interruptions of less than 14 days, the prior dose can be resumed immediately. Taking pirfenidone with food is essential: it reduces the incidence of nausea and dizziness, even though food lowers Cmax by ~49%. Total absorption (AUC) is only minimally reduced (~16%) with food, so efficacy is preserved. The 801 mg film-coated tablet greatly simplifies the maintenance regimen from 9 capsules to 3 tablets daily.
Pharmacology
Mechanism of Action
The precise mechanism by which pirfenidone treats IPF has not been fully established. Pirfenidone is a synthetic pyridone compound that exhibits combined anti-fibrotic, anti-inflammatory, and antioxidant properties. In animal models of pulmonary fibrosis, pirfenidone has been shown to reduce the production of key pro-fibrotic mediators, including transforming growth factor-beta (TGF-β), and suppress the synthesis of fibroblast growth factor. It also downregulates pro-inflammatory cytokines such as tumour necrosis factor-alpha and interleukins. More recently, in vitro studies have demonstrated that pirfenidone directly inhibits collagen fibril assembly. Unlike nintedanib, which targets specific receptor tyrosine kinases, pirfenidone appears to work through broader modulation of fibrotic and inflammatory signalling pathways, though neither drug reverses existing fibrosis.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Tmax ~0.5 h (fasted), ~3 h (with food); food reduces Cmax by ~49% and AUC by ~16%; absolute bioavailability not determined in humans | Must be taken with food to reduce GI side effects and dizziness; the Cmax reduction with food is clinically beneficial as peak-related AEs are mitigated without meaningful loss of total exposure |
| Distribution | Apparent Vd ~59–71 L; protein binding ~58% (albumin, concentration-independent over 1–10 µg/mL) | Moderate volume of distribution and relatively low protein binding (compared to nintedanib at 97.8%) allow wider distribution but also mean drug interactions at the protein-binding level are less clinically significant |
| Metabolism | Primarily CYP1A2 (70–80%); minor CYP2C9, 2C19, 2D6, 2E1; major metabolite: 5-carboxy-pirfenidone (metabolite:parent ratio ~0.6–0.7; not pharmacologically active) | Heavy reliance on CYP1A2 makes pirfenidone highly susceptible to CYP1A2 inhibitors (fluvoxamine: ~4× increase) and inducers (smoking: AUC reduced to 46% of nonsmokers); dose adjustments required with CYP1A2 inhibitors |
| Elimination | t½ ~3 hours; ~80% excreted in urine (predominantly as 5-carboxy metabolite; 99.6% of urinary drug is the metabolite); negligible parent drug in urine | Very short half-life necessitates TID dosing to maintain therapeutic levels; predominantly renal elimination of metabolites means caution in renal impairment (metabolite accumulates: AUC ↑5.6-fold in severe impairment) |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nausea | 36% vs 16% placebo | Most common AE; take with food; usually improves with continued therapy; dose reduction may help |
| Rash | 30% vs 10% placebo | Includes all rash types; most common reason for discontinuation alongside nausea; may be related to photosensitivity |
| Upper respiratory tract infection | 27% vs 25% placebo | Minimally above placebo; likely not causally related |
| Diarrhea | 26% vs 20% placebo | Less prominent than with nintedanib (62%); manage with anti-diarrheals and dose modification |
| Fatigue | 26% vs 19% placebo | May be disease-related; monitor for contribution to reduced activity |
| Abdominal pain | 24% vs 15% placebo | Includes upper/lower abdominal pain and stomach discomfort |
| Headache | 22% vs 19% placebo | Marginally above placebo |
| Decreased appetite | 21% vs 8% placebo | Contributes to weight loss (10% vs 5%); monitor nutritional status |
| Dyspepsia | 19% vs 7% placebo | One of the most common GI events leading to dose reduction |
| Dizziness | 18% vs 11% placebo | Taking with food helps reduce dizziness |
| Vomiting | 13% vs 6% placebo | Anti-emetics may be needed; consider dose reduction |
| GERD | 11% vs 7% placebo | PPIs or H2 blockers may help; elevate head of bed |
| Sinusitis | 11% vs 10% placebo | Marginally above placebo |
| Insomnia | 10% vs 7% placebo | Consider sleep hygiene counselling |
| Weight decreased | 10% vs 5% placebo | Related to nausea, decreased appetite, and GI symptoms; monitor weight regularly |
| Arthralgia | 10% vs 7% placebo | Marginally above placebo; generally mild |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Photosensitivity reaction | 9% vs 1% placebo | Unique to pirfenidone among ILD drugs; mostly in first 6 months; use SPF 50+, protective clothing; avoid sunlamps; avoid other photosensitizing drugs |
| Pruritus | 8% vs 5% placebo | May be related to rash or photosensitivity |
| Asthenia | 6% vs 4% placebo | Distinct from fatigue; may reflect more severe weakness |
| Dysgeusia | 6% vs 2% placebo | Altered taste; may contribute to decreased appetite |
| Non-cardiac chest pain | 5% vs 4% placebo | Rule out cardiac causes; marginally above placebo |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Drug-induced liver injury (DILI) | ALT/AST ≥3× ULN: 3.7% vs 0.8%; ≥10× ULN: 0.3% vs 0.2%; fatal cases postmarketing | Can occur at any time; monitor per protocol | LFTs at baseline, monthly × 6 months, then Q3 months; >3–5× ULN with symptoms or bilirubin: permanently discontinue; >5× ULN: permanently discontinue; do not rechallenge |
| Severe cutaneous adverse reactions (SCAR): SJS, TEN, DRESS | Rare (postmarketing) | Variable | Interrupt pirfenidone immediately; consult dermatology; if SCAR confirmed, permanently discontinue; do not rechallenge |
| Photosensitivity reaction (severe) | 9% overall; severe cases requiring dose change | Mostly first 6 months | Dose reduction or discontinuation; avoid sunlight/sunlamps; SPF 50+; avoid concomitant photosensitizing drugs |
| Agranulocytosis | Rare (postmarketing) | Variable | Monitor CBC if clinically indicated; discontinue if confirmed |
| Angioedema | Rare (postmarketing) | Variable | Discontinue; standard emergency management |
Photosensitivity reactions (9% vs 1% placebo) are unique to pirfenidone among anti-fibrotic agents and are not seen with nintedanib. They occur predominantly in the first 6 months. All patients must be counselled before starting therapy: use SPF 50 or higher sunscreen daily, wear long-sleeved clothing and a hat, avoid sunlamps and tanning beds, and avoid co-prescribing other photosensitizing medications. If a sunburn-like reaction develops, consider dose reduction. Severe photosensitivity may require treatment discontinuation.
Drug Interactions
Pirfenidone is metabolized primarily (70–80%) via CYP1A2, making it highly susceptible to drugs and behaviours that inhibit or induce this enzyme. Minor contributions come from CYP2C9, 2C19, 2D6, and 2E1. Pirfenidone itself shows weak in vitro inhibition of CYP enzymes and P-gp at high concentrations, but clinical significance has not been established.
Monitoring
-
Liver Function Tests
Baseline; monthly × 6 months; then Q3 months
Routine ALT, AST, and bilirubin. ALT/AST ≥3× ULN occurred in 3.7% vs 0.8% placebo. Fatal DILI reported postmarketing. If >3–5× ULN with symptoms/bilirubin: permanently discontinue, do not rechallenge. If >5× ULN: permanently discontinue. -
Skin Assessment
Each visit; especially first 6 months
Routine Photosensitivity (9% vs 1%) and rash (30% vs 10%) are the dominant dermatologic effects. Assess for new rash, sunburn-like reactions, and signs of SCAR (SJS, TEN, DRESS). Interrupt pirfenidone if SCAR suspected; permanently discontinue if confirmed. -
GI Tolerability
Each visit; first 3 months most critical
Routine Nausea (36%), diarrhea (26%), dyspepsia (19%), vomiting (13%), GERD (11%) are the most common GI events. GI events led to dose modification in 18.5% and discontinuation in 2.2%. Incidence highest in first 3 months. -
Weight
Each visit
Routine Weight loss (10% vs 5%) and decreased appetite (21% vs 8%) are common. Monitor nutritional status, especially in underweight or cachectic IPF patients. -
Drug Interactions
At initiation and any medication change
Trigger-based Review for CYP1A2 inhibitors (fluvoxamine, ciprofloxacin, enoxacin) and inducers (smoking). Fluvoxamine increases pirfenidone exposure up to 7-fold. Smoking reduces it by >50%. Dose adjustments required. -
Pulmonary Function
Q3–6 months
Routine Serial FVC to assess treatment response. ASCEND trial showed a reduction in FVC decline of ~193 mL vs placebo at 52 weeks. Continue therapy if decline rate is slower than predicted.
Contraindications & Cautions
Absolute Contraindications
- None formally listed in the FDA PI.
Relative Contraindications (Specialist Input Recommended)
- Severe hepatic impairment (Child-Pugh C) — pirfenidone is not recommended; safety, efficacy, and PK have not been studied in these patients.
- End-stage renal disease requiring dialysis — not recommended; PK not studied in ESRD on dialysis.
- Concomitant fluvoxamine or other strong CYP1A2 inhibitors — increases pirfenidone exposure up to 7-fold; should be discontinued before starting pirfenidone; if unavoidable, reduce pirfenidone dose to 267 mg TID.
Use with Caution
- Mild to moderate hepatic impairment (Child-Pugh A/B) — AUC increased ~1.6-fold in moderate impairment. Monitor for adverse reactions; consider dose modification or discontinuation as needed.
- Renal impairment (any degree) — pirfenidone AUC modestly increased; the 5-carboxy metabolite accumulates markedly (AUC 5.6-fold higher in severe impairment). Use with caution; monitor for adverse effects.
- Active smokers — smoking reduces pirfenidone AUC to 46% of nonsmoker levels, which may substantially reduce efficacy. Strongly encourage cessation before and during treatment.
- Pregnancy — insufficient human data. Not teratogenic in animals at up to 3× MRDD. Reduced pup viability at 3× MRDD in pre-/post-natal studies. Use only if benefit outweighs risk.
- Lactation — pirfenidone or metabolites excreted in rat milk. No human data. Consider developmental benefit of breastfeeding alongside clinical need for pirfenidone.
Pirfenidone does not carry a formal FDA Boxed Warning. However, the 2023 PI revision prominently warns about two serious risks: (1) Drug-induced liver injury, including fatal cases in the postmarketing period. ALT/AST ≥3× ULN occurred in 3.7% vs 0.8% of placebo-treated patients. Mandatory LFT monitoring is monthly for 6 months, then quarterly. (2) Severe cutaneous adverse reactions (SCAR), including SJS, TEN, and DRESS, reported in the postmarketing setting. If SCAR is suspected, interrupt pirfenidone immediately and consult dermatology. If confirmed, permanently discontinue.
Patient Counselling
Purpose of Therapy
Pirfenidone is an oral anti-fibrotic medication that slows the buildup of scar tissue in the lungs caused by IPF. It does not cure the disease or improve existing lung damage, but it helps slow the rate at which your breathing gets worse. You will need regular blood tests and lung function assessments throughout treatment.
How to Take
Take pirfenidone with food, three times a day at the same times each day (for example, breakfast, lunch, and dinner). You will start with a low dose during the first week, then increase over 2 weeks until you reach the full dose. The 801 mg tablet allows you to take just one tablet per dose instead of three capsules. If you miss a dose, do not take two doses at once. If you stop taking pirfenidone for 14 or more days, you will need to re-start the dose-building schedule.
Sources
- Esbriet (pirfenidone) capsules and film-coated tablets, for oral use. Full Prescribing Information. Genentech/Legacy Pharma. Revised 02/2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/208780s007,022535s016lbl.pdf Primary source for all dosing, indications, adverse reactions, warnings, DILI and SCAR data, PK parameters, and drug interaction information.
- King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083-2092. doi:10.1056/NEJMoa1402582 ASCEND trial (Study 1); pivotal 52-week phase 3 study demonstrating statistically significant reduction in FVC decline; source for primary efficacy endpoint data.
- Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011;377(9779):1760-1769. doi:10.1016/S0140-6736(11)60405-4 CAPACITY 1 and 2 trials (Studies 2 and 3); Study 2 showed significant FVC benefit at 72 weeks; Study 3 did not reach statistical significance; both contributed safety data for PI Table 2.
- Noble PW, Albera C, Bradford WZ, et al. Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials. Eur Respir J. 2016;47(1):243-253. doi:10.1183/13993003.00026-2015 Pooled analysis of ASCEND and CAPACITY trials providing integrated efficacy and safety data across all three phase 3 studies.
- Behr J, Prasse A, Kreuter M, et al. Pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis (RELIEF): a double-blind, randomised, placebo-controlled, phase 2b trial. Lancet Respir Med. 2021;9(5):476-486. doi:10.1016/S2213-2600(20)30554-3 RELIEF trial evaluating pirfenidone in non-IPF progressive fibrosing ILDs; showed reduced FVC decline but terminated early; source for off-label use evidence.
- Raghu G, Remy-Jardin M, Richeldi L, et al. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2022;205(9):e18-e47. doi:10.1164/rccm.202202-0399ST Joint ATS/ERS/JRS/ALAT guideline providing conditional recommendation for pirfenidone in IPF.
- Oku H, Shimizu T, Kawabata T, et al. Antifibrotic action of pirfenidone and prednisolone: different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis. Eur J Pharmacol. 2008;590(1-3):400-408. doi:10.1016/j.ejphar.2008.06.046 Preclinical study demonstrating pirfenidone’s effects on TGF-β, bFGF, and pro-inflammatory cytokines in a bleomycin lung fibrosis model.
- Knüppel L, Ishikawa Y, Aichler M, et al. A novel antifibrotic mechanism of nintedanib and pirfenidone: inhibition of collagen fibril assembly. Am J Respir Cell Mol Biol. 2017;57(1):77-90. doi:10.1165/rcmb.2016-0217OC In vitro study demonstrating that pirfenidone (and nintedanib) directly inhibit collagen fibril assembly, independent of transcription effects.
- Shi S, Wu J, Chen H, et al. Single- and multiple-dose pharmacokinetics of pirfenidone, an antifibrotic agent, in healthy Chinese volunteers. J Clin Pharmacol. 2007;47(10):1268-1276. doi:10.1177/0091270007304104 Clinical PK study providing single- and multiple-dose PK parameters including half-life (~3 h), Tmax, and dose proportionality data.
- Kim ES, Keating GM. Pirfenidone: a review of its use in idiopathic pulmonary fibrosis. Drugs. 2015;75(2):219-230. doi:10.1007/s40265-015-0350-9 Comprehensive clinical review covering pharmacology, PK, CYP1A2 interaction data, clinical efficacy, and safety profile of pirfenidone in IPF.
- Rubino CM, Bhavnani SM, Ambrose PG, et al. Effect of food and antacids on the pharmacokinetics of pirfenidone in older healthy adults. Pulm Pharmacol Ther. 2009;22(4):279-285. doi:10.1016/j.pupt.2009.03.003 PK study quantifying the effect of food on pirfenidone absorption (Cmax ↓49%, AUC ↓16%) and the clinical rationale for administration with food.