Pirfenidone is an oral pyridone for the treatment of idiopathic pulmonary fibrosis. During randomized, double-blind, placebo-controlled trials, pirfenidone significantly reduced decline in forced vital capacity (FVC). Differences in mean decline in FVC over time between treatment groups ranged from 157 to 193 mL. All-cause mortality was not significantly affected by pirfenidone across clinical trials and available follow-up periods. Liver enzyme elevations and drug-induced liver injury have been associated with pirfenidone; therefore, liver function monitoring is necessary during therapy. Pirfenidone was FDA-approved in 2014.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Doses should be taken with food at the same time each day.
The safety of pirfenidone in patients with idiopathic pulmonary fibrosis was evaluated in 3 randomized, double-blind, placebo-controlled trials, in which 623 of 1,247 patients received pirfenidone. Nausea was a common reaction, occurring in 36% of patients who received pirfenidone vs. 16% of those who received placebo. Nausea was a common reason for drug discontinuation, treatment interruption, or dosage reduction. Diarrhea was another common adverse reaction to pirfenidone that led to treatment interruption or dosage reduction, occurring in 26% of pirfenidone-treated patients vs. 20% of placebo-treated patients. The following gastrointestinal (GI) adverse reactions were also reported more often in patients treated with pirfenidone compared with placebo: abdominal pain (24% vs. 15%), dyspepsia (19% vs. 7%), vomiting (13% vs. 6%), gastroesophageal reflux (11% vs. 7%), decreased appetite (21% vs. 8%, synonym: anorexia), dysgeusia (6% vs. 2%), and weight loss (10% vs. 5%). The incidence of GI adverse reactions was highest early in the course of treatment (during the initial 3 months of treatment) and decreased over time. Dosage reduction or treatment interruption because of GI adverse reactions was necessary in 18.5% of patients taking pirfenidone compared to 5.8% of patients taking placebo. Dose reduction or treatment interruptions may be required.
The safety of pirfenidone in patients with idiopathic pulmonary fibrosis was evaluated in 3 randomized, double-blind, placebo-controlled trials, in which 623 of 1,247 patients received pirfenidone. More patients treated with pirfenidone experienced photosensitivity reactions than those treated with placebo (9% vs. 1%). Rash (unspecified) was observed in 30% of pirfenidone-treated patients vs. 10% of placebo-treated patients. Both rash and photosensitivity reactions led to dosage reductions or treatment interruption. Most photosensitivity reactions occurred during the initial 6 months of therapy. Pruritus also occurred in 8% of patients during clinical trials. Patients should avoid or minimize sunlight (UV) exposure, including sunlamps, while using pirfenidone, as well as protect themselves by using a sunblock (SPF 50 or more) or by wearing clothing that protects against sun exposure. Dosage reduction or discontinuation may be necessary if photosensitivity reactions or rash occurs. During postmarketing experience with pirfenidone, angioedema has been observed.
Pirfenidone was evaluated in 3 randomized, double-blind, placebo-controlled trials in patients with idiopathic pulmonary fibrosis. Headache was reported in 22% of patients treated with pirfenidone (n = 623) compared with 19% of those who received placebo (n = 624). Dizziness and insomnia also occurred more frequently with pirfenidone compared to placebo with incidence rates of 18% and 10%, respectively.
Pirfenidone was evaluated in 3 randomized, double-blind, placebo-controlled trials in patients with idiopathic pulmonary fibrosis (n = 1,247). Respiratory infections had similar incidence rates across pirfenidone and placebo groups, including upper respiratory tract infection (27% pirfenidone vs. 25% placebo) and sinusitis (11% pirfenidone vs. 10% placebo).
The safety of pirfenidone in patients with idiopathic pulmonary fibrosis was evaluated in 3 randomized, double-blind, placebo-controlled trials, in which 623 of 1,247 patients received pirfenidone. Systemic adverse reactions reported more frequently with pirfenidone compared to placebo include fatigue (26% vs. 19%) and asthenia (6% vs. 4%). Arthralgia was also reported in 10% of pirfenidone-treated patients compared to 7% of those treated with placebo.
Cases of drug-induced liver injury (DILI) have been reported with pirfenidone; prescribers should monitor patients for hepatotoxicity. During the 3 clinical trials of pirfenidone for idiopathic pulmonary fibrosis, elevated hepatic enzymes [where ALT or AST was 3 times the upper limit of normal (ULN)] were reported in 3.7% of treated patients vs. 0.8% of patients who received placebo (n = 624). These enzyme elevations were reversible with dose modification or interruption and were not associated with clinical signs or symptoms of liver injury. Hyperbilirubinemia, in combination with increases in ALT and/or AST, has been observed postmarketing, and non-serious and serious cases of DILI, including severe liver injury with fatal outcome, have been reported. Liver function tests (LFTs) should be monitored before starting treatment with pirfenidone, monthly for 6 months, every 3 months thereafter and as clinically indicated. Measure LFTs promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Dose modifications or interruption of therapy may be necessary for liver enzyme elevations.
The safety of pirfenidone was evaluated in 3 randomized, double-blind, placebo-controlled trials in patients with idiopathic pulmonary fibrosis. Non-cardiac chest pain (unspecified) was reported in 5% of patients treated with pirfenidone (n = 623) compared to 4% of those who received placebo (n = 624).
Agranulocytosis has been observed during postmarketing experience with pirfenidone.
Postmarketing reports of severe cutaneous adverse reactions (SCAR) have been reported and include: Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS). Treatment should be interrupted if signs and symptoms of SCAR occur. Permanent discontinuation of the treatment is required if SCAR diagnosis is confirmed.
Use pirfenidone with caution in patients with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic disease due to a risk for hepatotoxicity. Pirfenidone is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C). Cases of drug-induced liver injury (DILI) have been observed with pirfenidone. In the postmarketing period, non-serious and serious cases of DILI, including severe liver injury with fatal outcome, have been reported. Increases in ALT and AST greater than 3 times the upper level of normal (ULN), as well as some cases of hyperbilirubinemia, have been reported during treatment. Patients with hyperbilirubinemia and ALT and/or AST more than 3 times the ULN up to 5 times the ULN should not receive pirfenidone. Patients with ALT and/or AST greater than 5 times the ULN should also not receive pirfenidone. Such patients may include those with jaundice, cholestasis, or hepatitis. Close monitoring of hepatic function is recommended for all patients. ALT, AST, and bilirubin must be monitored before therapy, then monthly for 6 months, and every 3 months after that. Measure liver function tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Dosage modifications, treatment interruption, or discontinuation may be necessary to allow for hepatic enzyme recovery.
Use pirfenidone with caution in patients with renal disease, including 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. Systemic exposure to pirfenidone increases with declining renal function, therefore increasing the risk for adverse effects. Specific guidelines for dosage adjustments in renal impairment are not available; the daily dosage may be maintained, reduced, or interrupted as clinically appropriate. Use in patients who have renal failure requiring dialysis is not recommended.
Patients should stop smoking prior to pirfenidone therapy initiation and avoid smoking during treatment. Tobacco smoking decreases exposure to pirfenidone, which may alter efficacy.
Patients should avoid or minimize sunlight (UV) exposure, including sunlamps, while using pirfenidone, as photosensitivity reactions or rash have been associated with therapy. Patients should protect themselves by using a sunblock (SPF 50 or greater) or by wearing clothing that protects against sun exposure. Most reactions were reported in the first 6 months of therapy. Dosage reduction or discontinuation may be necessary if photosensitivity reactions occur.
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.
Postmarketing cases of serious rash, specifically, severe cutaneous adverse reactions (SCAR) have been reported with pirfenidone. Reported reactions include: Steven-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS). Patients should be advised to report any signs and symptoms of SCAR such as, rash, skin blisters, and sores in the mouth. Treatment should be interrupted if SCAR is suspected and discontinued permanently if a SCAR diagnosis is confirmed.
General Dosing Information
-Prior to treatment initiation, conduct liver function tests (ALT, AST, and bilirubin), then monthly during the first 6 months, followed by every 3 months thereafter. Dosage adjustments, interruption, or discontinuation may be necessary for elevated liver enzymes.
-Dosage modifications due to adverse reactions may be necessary. If significant photosensitivity, rash, or gastrointestinal reactions occur, consider temporary dosage reduction or treatment interruption to allow for symptom resolution.
-If 14 or more days of treatment are missed, re-initiate treatment with the 2-week dosage titration up to the full maintenance dosage. For treatment interruption of less than 14 days, resume treatment with the prior dosage.
For the treatment of idiopathic pulmonary fibrosis:
Oral dosage:
Adults: 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.
Maximum Dosage Limits:
-Adults
2,403 mg/day PO.
-Geriatric
2,403 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
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.
Patients with Renal Impairment Dosing
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).
*non-FDA-approved indication
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.
Bictegravir; Emtricitabine; 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.
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. (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.
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. (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.
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.
Emtricitabine; Rilpivirine; 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.
Emtricitabine; 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.
Enasidenib: (Major) Avoid concomitant use of pirfenidone and enasidenib due to the increased risk for pirfenidone-related adverse effects and exposure. Pirfenidone is primarily metabolized by CYP1A2 with minor contributions from CYP2C9, CYP2C19, CYP2D6, and CYP2E1; enasidenib is a strong CYP1A2 inhibitor and weak CYP2C19 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.
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.
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.
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.
-Route-Specific Pharmacokinetics
Oral Route
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.
-Special Populations
Hepatic Impairment
Exposure to pirfenidone was increased in 12 subjects with moderate hepatic impairment (Child Pugh Class B) compared to 12 subjects with normal hepatic function. The mean AUC and Cmax of pirfenidone increased 1.6 and 1.4-fold, respectively, in subjects with hepatic impairment. Exposure to the 5-carboxy metabolite did not change significantly.
Renal Impairment
Exposure to pirfenidone and the 5-carboxy metabolite was increased in 18 subjects with mild (CrCl 50 to 80 mL/minute), moderate (CrCl 30 to 50 mL/minute), and severe (CrCl less than 30 mL/minute) renal impairment compared to 6 subjects with normal renal function (CrCl more than 80 mL/minute). The AUC of pirfenidone increased 1.4, 1.5, and 1.2-fold in subjects with mild, moderate, and severe renal impairment, respectively. The AUC of 5-carboxy-pirfenidone increased 1.7, 3.4, and 5.6-fold in subjects with mild, moderate, and severe impairment.
Geriatric
Clinically significant age-related differences in pirfenidone pharmacokinetics have not been observed. No dosage adjustment is necessary based on age alone.
Gender Differences
Clinically significant gender-related differences in pirfenidone pharmacokinetics have not been observed.
Ethnic Differences
Clinically significant ethnicity-related differences in pirfenidone pharmacokinetics have not been observed.
Obesity
Clinically significant weight-related differences in pirfenidone pharmacokinetics have not been observed.
Other
Tobacco Smoking
Systemic exposure to pirfenidone was significantly lower in smokers compared to nonsmokers following a single oral dose of 801 mg; the AUC and Cmax in smokers were 46% and 68%, respectively, of the values observed in nonsmokers. Because lowered exposure may decrease drug efficacy, patients should stop smoking prior to treatment and continue to avoid smoking when taking pirfenidone.