ESBRIET

Idiopathic Pulmonary Fibrosis Agents

Doses should be taken with food at the same time each day.

hepatotoxicity / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known

chest pain (unspecified) / Early / 5.0-5.0
elevated hepatic enzymes / Delayed / 3.7-3.7
jaundice / Delayed / Incidence not known
hyperbilirubinemia / Delayed / Incidence not known

nausea / Early / 36.0-36.0
rash / Early / 30.0-30.0
infection / Delayed / 27.0-27.0
diarrhea / Early / 26.0-26.0
fatigue / Early / 26.0-26.0
abdominal pain / Early / 24.0-24.0
headache / Early / 22.0-22.0
anorexia / Delayed / 21.0-21.0
dyspepsia / Early / 19.0-19.0
dizziness / Early / 18.0-18.0
vomiting / Early / 13.0-13.0
gastroesophageal reflux / Delayed / 11.0-11.0
sinusitis / Delayed / 11.0-11.0
weight loss / Delayed / 10.0-10.0
insomnia / Early / 10.0-10.0
arthralgia / Delayed / 10.0-10.0
photosensitivity / Delayed / 9.0-9.0
pruritus / Rapid / 8.0-8.0
dysgeusia / Early / 6.0-6.0
asthenia / Delayed / 6.0-6.0

ESBRIET

Rx

Oral pyridone agent used for idiopathic pulmonary fibrosis
Significantly reduced decline in forced vital capacity (FVC)
Monitoring of hepatic enzymes necessary during therapy; drug is associated with liver injury

Titrate dosage over 2 weeks to a maintenance dosage of 801 mg PO 3 times daily. Administer 267 mg PO 3 times daily on days 1 to 7. Then, 534 mg PO 3 times daily on days 8 to 14, followed by 801 mg PO 3 times daily from day 15 onward. Doses should be taken with food at the same time each day.

Use is not recommended in patients with severe hepatic impairment (Child Pugh Class C). Use with caution in patients with mild or moderate hepatic impairment (Child Pugh Class A or B).
For liver enzyme elevations, modify the dose as follows:
ALT and/or AST greater than 3 and up to 5 times the ULN without hyperbilirubinema: Maintain, if clinically appropriate, or reduce or interrupt dosing until liver function tests are within normal limits.
ALT and /or AST greater than 3 and up to 5 times the ULN with hyperbilirubinema: Permanently discontinue pirfenidone and do not rechallenge the patient.
ALT and/or AST greater than 5 times the ULN: Permanently discontinue pirfenidone and do not rechallenge the patient.

Use with caution in patients with mild (CrCl 50 to 80 mL/minute), moderate (CrCl 30 to 50 mL/minute), or severe (CrCl less than 30 mL/minute) renal impairment. Specific guidelines for dosage adjustments in renal impairment are not available; the daily dosage may be maintained, reduced, or interrupted as clinically appropriate.
 
Intermittent Hemodialysis
Use is not recommended in patients with end-stage renal disease requiring dialysis.
 
Other Dosage Adjustments
Avoid concomitant treatment with strong CYP1A2 inhibitors due to increases in pirfenidone exposure. If a strong CYP1A2 inhibitor is the only drug of choice available, reduce the pirfenidone dosage to 267 mg 3 times daily. If concurrent treatment with a moderate inhibitor of CYP1A2 cannot be avoided, reduce the pirfenidone dosage to 534 mg 3 times daily. Monitor closely for adverse reactions and consider discontinuation, if necessary.
Avoid the use of drugs or drug combinations that are moderate or strong inhibitors of CYP1A2 and 1 or more of the other CYP isoenzymes involved in pirfenidone metabolism (CYP2C9, CYP2C19, CYP2D6, and CYP2E1).

Amiodarone: (Major) Avoid the coadministration of amiodarone and pirfenidone. Concomitant use may result in increased plasma concentrations of pirfenidone. Pirfenidone is primarily metabolized by CYP1A2 with minor contributions from CYP2C9, CYP2C19, CYP2D6, and CYP2E1 and should not be used concomitantly with drugs that are moderate or strong inhibitors of both CYP1A2 and another enzyme involved in its metabolism. Amiodarone inhibits CYP1A2, CYP2C9, and CYP2D6.
Aprepitant, Fosaprepitant: (Minor) Use caution if pirfenidone and aprepitant are used concurrently and monitor for a possible decrease in the efficacy of pirfenidone. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Pirfenidone is a CYP2C9 substrate and aprepitant is a CYP2C9 inducer. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant. When a 3-day regimen of aprepitant (125 mg/80 mg/80 mg) given to healthy patients on stabilized chronic warfarin therapy (another CYP2C9 substrate), a 34% decrease in S-warfarin trough concentrations was noted, accompanied by a 14% decrease in the INR at five days after completion of aprepitant. Pirfenidone is also a weak in vitro CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur. Information is not available regarding the use of aprepitant with weak CYP3A4 inhibitors.
Atazanavir: (Moderate) Caution is warranted when atazanavir is administered with pirfenidone as there is a potential for elevated concentrations of atazanavir. Clinical monitoring for adverse effects is recommended during coadministration. Atazanavir is a substrate CYP3A4. Pirfenidone is a CYP3A4 inhibitor.
Atazanavir; Cobicistat: (Moderate) Caution is warranted when atazanavir is administered with pirfenidone as there is a potential for elevated concentrations of atazanavir. Clinical monitoring for adverse effects is recommended during coadministration. Atazanavir is a substrate CYP3A4. Pirfenidone is a CYP3A4 inhibitor. (Moderate) Caution is warranted when cobicistat is administered with pirfenidone as there is a potential for elevated concentrations of both drugs. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a substrate/inhibitor of CYP3A4 and CYP2D6. Pirfenidone is a substrate/inhibitor of CYP2D6 and a CYP3A4 inhibitor.
Carbamazepine: (Major) Discontinue carbamazepine prior to beginning pirfenidone, and avoid coadministration because it may decrease exposure to pirfenidone and compromise efficacy. Carbamazepine is a potent inducer of CYP1A2, CYP2C9, and CYP2C19. Pirfenidone is primarily metabolized by CYP1A2 with minor contributions from CYP2C9, CYP2C19, CYP2D6, and CYP2E1.
Cimetidine: (Major) Discontinue cimetidine prior to beginning pirfenidone because it may increase exposure to pirfenidone. Cimetidine is a moderate inhibitor of CYP1A2, CYP2C19, and to a lesser extent CYP2D6. Pirfenidone is primarily metabolized by CYP1A2 with minor contributions from CYP2C9, CYP2C19, CYP2D6, and CYP2E1.
Ciprofloxacin: (Major) Avoid concomitant administration of ciprofloxacin and pirfenidone because it increases exposure to pirfenidone. If concurrent use cannot be avoided, it is recommended with the use of ciprofloxacin at a dosage of 750 mg twice daily that the maintenance dose of pirfenidone be reduced to 534 mg PO 3 times daily. Careful monitoring is suggested when ciprofloxacin is used at a dosage of 250 mg or 500 mg daily. Monitor for adverse effects of pirfenidone, like elevated hepatic enzymes, arthralgia, or nausea. Ciprofloxacin is a moderate inhibitor of CYP1A2, and pirfenidone is primarily metabolized by CYP1A2. In a single-dose study, coadministration of pirfenidone 801 mg and ciprofloxacin, which was dosed at 750 mg twice daily from days 2 to 7, on day 6 increased pirfenidone exposure by 81%.
Citalopram: (Minor) The plasma concentration of citalopram, a CYP2C19 substrate, may be increased when administered concurrently with pirfenidone, a weak in vitro CYP2C19 inhibitor. Because citalopram causes dose-dependent QT prolongation, the maximum daily dose should not exceed 20 mg per day in patients receiving CYP2C19 inhibitors.
Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with pirfenidone as there is a potential for elevated concentrations of both drugs. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a substrate/inhibitor of CYP3A4 and CYP2D6. Pirfenidone is a substrate/inhibitor of CYP2D6 and a CYP3A4 inhibitor.
Cobimetinib: (Moderate) If concurrent use of cobimetinib and pirfenidone is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro as well as a P-glycoprotein (P-gp) substrate; pirfenidone is a weak in vitro inhibitor of both CYP3A and P-gp. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with pirfenidone, a weak P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like pirfenidone in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with pirfenidone, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
Darunavir: (Moderate) Caution is warranted when darunavir is administered with pirfenidone as there is a potential for elevated concentrations of both drugs. Clinical monitoring for adverse effects is recommended during coadministration. Darunavir is a substrate/inhibitor of CYP3A4 and a CYP2D6 inhibitor. Pirfenidone is a substrate/inhibitor of CYP2D6 and a CYP3A4 inhibitor.
Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with pirfenidone as there is a potential for elevated concentrations of both drugs. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a substrate/inhibitor of CYP3A4 and CYP2D6. Pirfenidone is a substrate/inhibitor of CYP2D6 and a CYP3A4 inhibitor. (Moderate) Caution is warranted when darunavir is administered with pirfenidone as there is a potential for elevated concentrations of both drugs. Clinical monitoring for adverse effects is recommended during coadministration. Darunavir is a substrate/inhibitor of CYP3A4 and a CYP2D6 inhibitor. Pirfenidone is a substrate/inhibitor of CYP2D6 and a CYP3A4 inhibitor.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is warranted when cobicistat is administered with pirfenidone as there is a potential for elevated concentrations of both drugs. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a substrate/inhibitor of CYP3A4 and CYP2D6. Pirfenidone is a substrate/inhibitor of CYP2D6 and a CYP3A4 inhibitor. (Moderate) Caution is warranted when darunavir is administered with pirfenidone as there is a potential for elevated concentrations of both drugs. Clinical monitoring for adverse effects is recommended during coadministration. Darunavir is a substrate/inhibitor of CYP3A4 and a CYP2D6 inhibitor. Pirfenidone is a substrate/inhibitor of CYP2D6 and a CYP3A4 inhibitor.
Disulfiram: (Major) Discontinue disulfiram prior to beginning pirfenidone because it may increase exposure to pirfenidone. Disulfiram is a moderate inhibitor of CYP1A2 and a potent inhibitor of CYP2E1. Pirfenidone is primarily metabolized by CYP1A2 with minor contributions from CYP2C9, CYP2C19, CYP2D6, and CYP2E1.
Dronabinol: (Moderate) Use caution if coadministration of dronabinol with pirfenidone is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; pirfenidone is a weak inhibitor of CYP2C9 and 3A4 in vitro. Concomitant use may result in elevated plasma concentrations of dronabinol.
Edoxaban: (Moderate) Coadministration of edoxaban and pirfenidone may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and in vitro data indicate pirfenidone is a mild P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of pirfenidone; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
Elbasvir; Grazoprevir: (Moderate) Administering elbasvir; grazoprevir with pirfenidone may cause the plasma concentrations of elbasvir and grazoprevir to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Pirfenidone is a mild inhibitor of CYP3A; both elbasvir and grazoprevir are metabolized by CYP3A. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with pirfenidone as there is a potential for elevated concentrations of both drugs. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a substrate/inhibitor of CYP3A4 and CYP2D6. Pirfenidone is a substrate/inhibitor of CYP2D6 and a CYP3A4 inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with pirfenidone as there is a potential for elevated concentrations of both drugs. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a substrate/inhibitor of CYP3A4 and CYP2D6. Pirfenidone is a substrate/inhibitor of CYP2D6 and a CYP3A4 inhibitor.
Fluvoxamine: (Major) Discontinue fluvoxamine prior to beginning pirfenidone, and avoid coadministration because it significantly increases exposure to pirfenidone. If fluvoxamine is the only drug of choice, it is recommended that the maintenance dose of pirfenidone be reduced to 267 mg PO 3 times daily. Monitor for adverse effects of pirfenidone, like elevated hepatic enzymes, arthralgia, or nausea. Fluvoxamine is a potent inhibitor of CYP1A2, a potent inhibitor of CYP2C19, and a mild inhibitor of CYP2C9. Pirfenidone is primarily metabolized by CYP1A2 with minor contributions from CYP2C9, CYP2C19, CYP2D6, and CYP2E1. In a single-dose study, pirfenidone was coadministered with fluvoxamine (50 mg at bedtime for 3 days; 50 mg twice a day for 3 days, and 50 mg in the morning and 100 mg at bedtime for 4 days); an approximate 4-fold increase in pirfenidone exposure in nonsmokers and 7-fold increase in smokers was observed.
Fosamprenavir: (Moderate) Concomitant use of pirfenidone and fosamprenavir may result in elevated fosamprenavir plasma concentrations. Pirfenidone is a mild in vitro inhibitor of the hepatic isoenzymes CYP2C9, CYP2D6, and CYP3A4, and an inhibitor of the drug transporter P-glycoprotein (P-gp). Amprenavir, the active metabolite of fosamprenavir, is substrate of P-gp, CYP2C9, CYP2D6, and CYP3A4.
Lesinurad: (Moderate) Use lesinurad and pirfenidone together with caution; pirfenidone may increase the systemic exposure of lesinurad. Pirfenidone is a mild inhibitor of CYP2C9 in vitro, and lesinurad is a CYP2C9 substrate.
Lesinurad; Allopurinol: (Moderate) Use lesinurad and pirfenidone together with caution; pirfenidone may increase the systemic exposure of lesinurad. Pirfenidone is a mild inhibitor of CYP2C9 in vitro, and lesinurad is a CYP2C9 substrate.
Lopinavir; Ritonavir: (Moderate) Concurrent administration of pirfenidone with ritonavir may result in elevated plasma concentrations of ritonavir. Pirfenidone is a mild inhibitor of CYP3A4 and the drug transporter P-glycoprotein (P-gp); ritonavir is a substrate of both CYP3A4 and P-gp. Monitor for antiviral adverse effects if these drugs are administered together.
Maraviroc: (Minor) Use caution and closely monitor for increased adverse effects with the coadministration of maraviroc and pirfenidone as increased maraviroc concentrations may occur. Maraviroc is a substrate of CYP3A and P-glycoprotein (P-gp); pirfenidone is a weak inhibitor of CYP3A4 and P-gp. The effects of P-gp on the concentrations of maraviroc are unknown, although an increase in concentrations and thus, toxicity, are possible.
Mexiletine: (Major) Avoid concomitant administration of mexilitine and pirfenidone because it may increase exposure to pirfenidone. If concurrent use cannot be avoided, closely monitor for adverse effects of pirfenidone, like elevated hepatic enzymes, arthralgia, or nausea. Dosage redution, interruption of therapy, or discontinuation may be necessary. Mexiletine is a moderate inhibitor of CYP1A2, and pirfenidone is primarily metabolized by CYP1A2.
Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as pirfenidone may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
Nebivolol: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with pirfenidone. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as pirfenidone, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
Nebivolol; Valsartan: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with pirfenidone. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as pirfenidone, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
Nirmatrelvir; Ritonavir: (Moderate) Concurrent administration of pirfenidone with ritonavir may result in elevated plasma concentrations of ritonavir. Pirfenidone is a mild inhibitor of CYP3A4 and the drug transporter P-glycoprotein (P-gp); ritonavir is a substrate of both CYP3A4 and P-gp. Monitor for antiviral adverse effects if these drugs are administered together.
Osilodrostat: (Major) Reduce the dose of pirfenidone to 534 mg three times daily (1,602 mg/day) if coadministration with osilodrostat is necessary. Concurrent use may increase pirfenidone exposure. Pirfenidone is a CYP1A2 substrate and osilodrostat is a moderate CYP1A2 inhibitor. Coadministration with another moderate CYP1A2 inhibitor increased pirfenidone exposure by 81%.
Paroxetine: (Moderate) Pirfenidone is primarily metabolized by CYP1A2 with minor contributions from other CYP isoenzymes including CYP2D6. Paroxetine is a potent inhibitor of CYP2D6. Because pirfenidone is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events and should be approached with caution.
Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to pirfenidone if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP1A2 and CYP2D6 inhibitor, while pirfenidone is a substrate of both these enzymes.
Porfimer: (Major) Avoid coadministration of porfimer with pirfenidone due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like pirfenidone may increase the risk of a photosensitivity reaction.
Ritonavir: (Moderate) Concurrent administration of pirfenidone with ritonavir may result in elevated plasma concentrations of ritonavir. Pirfenidone is a mild inhibitor of CYP3A4 and the drug transporter P-glycoprotein (P-gp); ritonavir is a substrate of both CYP3A4 and P-gp. Monitor for antiviral adverse effects if these drugs are administered together.
Rolapitant: (Major) Use caution if pirfenidone and rolapitant are used concurrently, and monitor for pirfenidone-related adverse effects. Pirfenidone is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
Rucaparib: (Major) Reduce the dose of pirfenidone to 534 mg three times daily (1,602 mg/day) if coadministration with rucaparib is necessary. Pirfenidone is a CYP1A2 substrate and rucaparib is a moderate CYP1A2 inhibitor. Coadministration with another moderate CYP1A2 inhibitor increased pirfenidone exposure by 81%.
Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with pirfenidone. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); pirfenidone is a weak inhibitor of P-gp. Pirfenidone is also a weak in vitro inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with pirfenidone. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); pirfenidone is a weak inhibitor of P-gp. Pirfenidone is also a weak in vitro inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
Tenofovir Alafenamide: (Moderate) Close clinical monitoring for adverse events is advised when administering tenofovir alafenamide with pirfenidone. Use of these drugs together may result in elevated tenofovir plasma concentrations. Pirfenidone is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
Vemurafenib: (Major) Discontinue vemurafenib prior to beginning pirfenidone because it may increase exposure to pirfenidone. Vemurafenib is a moderate inhibitor of CYP1A2, CYP2C9, and to a lesser extent CYP2D6. Pirfenidone is primarily metabolized by CYP1A2 with minor contributions from CYP2C9, CYP2C19, CYP2D6, and CYP2E1.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with pirfenidone is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like pirfenidone may increase the risk of a photosensitivity reaction.
Viloxazine: (Major) Avoid concomitant use of viloxazine and pirfenidone due to the increased risk for pirfenidone-related adverse effects and exposure. Pirfenidone is a CYP1A2 substrate and viloxazine is a strong CYP1A2 inhibitor.
Zafirlukast: (Major) Discontinue zafirlukast prior to beginning pirfenidone because it significantly increases exposure to pirfenidone. Zafirlukast is a moderate inhibitor of CYP1A2 and CYP2C9. Pirfenidone is primarily metabolized by CYP1A2 with minor contributions from CYP2C9, CYP2C19, CYP2D6, and CYP2E1.
Zileuton: (Major) Avoid concomitant administration of zileuton and pirfenidone because it may increase exposure to pirfenidone. If concurrent use cannot be avoided, closely monitor for adverse effects of pirfenidone, like elevated hepatic enzymes, arthralgia, or nausea. Dosage redution, interruption of therapy, or discontinuation may be necessary. Zileuton is a moderate inhibitor of CYP1A2, and pirfenidone is primarily metabolized by CYP1A2.

ESBRIET/Pirfenidone Oral Cap: 267mg
ESBRIET/Pirfenidone Oral Tab: 267mg, 534mg, 801mg

2,403 mg/day PO.

2,403 mg/day PO.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

The anti-fibrotic action of pirfenidone may be due to inhibition of the production of reactive oxygen species, pro-fibrotic cytokines, like transforming growth factor-beta (TGF-beta), and inflammatory cytokines, like tumor necrosis factor-alpha (TNF-alpha). Suppression of TGF-beta, which facilitates fibrotic processes in the lungs by inducing proliferation of macrophages and fibroblasts through platelet-derived growth factor (PGDF) expression, is considered the main mechanism of anti-fibrotic activity for pirfenidone. Pirfenidone has little immunosuppressive activity.

Pirfenidone is administered orally. Pirfenidone binds to plasma proteins in a concentration-independent manner with mean binding of 58%. Serum albumin is the major binding protein. Pirfenidone is primarily metabolized in the liver by CYP1A2 to 4 metabolites. Other enzymes including CYP2C9, CYP2C19, CYP2D6, and CYP2E1 are also involved. Only pirfenidone and the 5-carboxy-pirfenidone metabolite are present in human plasma in significant quantities. Approximately 80% of a dose is excreted in the urine, almost entirely as the 5-carboxy metabolite (99.6%). The mean terminal half-life is approximately 3 hours.
 
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, P-glycoprotein (P-gp)
Pirfenidone is a primary substrate of CYP1A2, as well as a minor substrate of CYP2C9, CYP2C19, CYP2D6, and CYP2E1. Dosage adjustments are required in patients taking strong or moderate CYP1A2 inhibitors (e.g., fluvoxamine, some quinolone antibiotics). Pirfenidone is a weak inhibitor of P-gp in vitro and inhibited CYP2C9, CYP2C19, CYP1A2, CYP2D6, and CYP3A4 in a concentration-dependent manner in vitro.

Maximum plasma concentration (Cmax) is observed between 30 minutes and 4 hours after single dose (801 mg). Food decreases the rate and extent of absorption, with median time to maximal concentration (Tmax) increased from 0.5 hours to 3 hours, maximum plasma concentration (Cmax) decreased by 49%, and AUC decreased by 16%. A reduced incidence of adverse reactions was observed in the fed group when compared to the fasted group. In controlled studies with idiopathic pulmonary fibrosis (IPF) patients, pirfenidone was taken with food.

The data with pirfenidone use during human pregnancy are insufficient to inform regarding drug associated risks for major birth defects and miscarriage. In animal reproduction studies, pirfenidone was not teratogenic in rats and rabbits at oral doses up to 3 and 2 times, respectively, the maximum recommended daily dose (MRDD) in adults. Use pirfenidone during pregnancy only if the benefits of treatment to the mother outweigh the potential risks to the fetus.

No information is available on the presence of pirfenidone in human milk, the effects of the drug on the breast-fed infant, or the effects of the drug on milk production. The lack of clinical data during breast-feeding precludes clear determination of the risk of pirfenidone to an infant during lactation; therefore, the developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for pirfenidone and the potential adverse effects on the breast-fed infant from pirfenidone or from the underlying maternal condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.