These Highlights Do Not Include All The Information Needed To Use Esbriet Safely And Effectively. See Full Prescribing Information For Esbriet.

Dosage Modification due to Elevated Liver Enzymes

Dosage modifications or interruptions may also be necessary when liver enzyme and bilirubin elevations are exhibited. For liver enzyme elevations, modify the dosage as follows:

If a patient exhibits >3 but ≤5 × the upper limit of normal (ULN) ALT and/or AST without symptoms or hyperbilirubinemia after starting ESBRIET therapy:

• Discontinue confounding medications, exclude other causes, and monitor the patient closely.
• Repeat liver chemistry tests as clinically indicated.
• The full daily dosage may be maintained, if clinically appropriate, or reduced or interrupted (e.g., until liver chemistry tests are within normal limits) with subsequent re-titration to the full dosage as tolerated.

If a patient exhibits >3 but ≤5 × ULN ALT and/or AST accompanied by symptoms or hyperbilirubinemia:

• Permanently discontinue ESBRIET.
• Do not rechallenge patient with ESBRIET.

If a patient exhibits >5 × ULN ALT and/or AST:

• Permanently discontinue ESBRIET.
• Do not rechallenge patient with ESBRIET.

Representative sample of labeling (see the HOW SUPPLIEDsection for complete listing):

Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) (see USP Controlled Room Temperature).

Keep the bottle tightly closed. Do not use if the seal over the bottle opening is broken or missing. Safely throw away any ESBRIET that is out of date or no longer needed.

Smoking causes decreased exposure to ESBRIET [see Clinical Pharmacology (12.3)], which may alter the efficacy profile of ESBRIET. Instruct patients to stop smoking prior to treatment with ESBRIET and to avoid smoking when using ESBRIET.

There is limited clinical experience with overdosage. Multiple dosages of ESBRIET up to a maximum tolerated dose of 4005 mg per day were administered as five 267 mg capsules three times daily to healthy adult volunteers over a 12-day dose escalation.

In the event of a suspected overdosage, appropriate supportive medical care should be provided, including monitoring of vital signs and observation of the clinical status of the patient.

ESBRIET belongs to the chemical class of pyridone. ESBRIET is available as a white to off-white hard gelatin capsule containing 267 mg of pirfenidone for oral administration, or, as film-coated tablets containing 267 mg (yellow) and 801 mg (brown) pirfenidone.

Pirfenidone has a molecular formula of C ₁₂H ₁₁NO and a molecular weight of 185.23. Pirfenidone has the following structural formula, which has been referred to as 5-methyl-1-phenyl-2-1(H)-pyridone or 5-methyl-1-phenyl-2-(1H)-pyridone.

Pirfenidone is a white to pale yellow, non-hygroscopic powder. It is more soluble in methanol, ethyl alcohol, acetone and chloroform than in water and 1.0 N HCl. The melting point is approximately 109°C.

ESBRIET capsule contains pirfenidone and the following inactive ingredients: microcrystalline cellulose, croscarmellose sodium, povidone, and magnesium stearate.

In addition, the capsule shell contains gelatin and titanium dioxide. The capsule brown printing ink includes shellac, iron oxide black, iron oxide red, iron oxide yellow, propylene glycol, ammonium hydroxide.

ESBRIET tablets contain pirfenidone and the following inactive ingredients: Microcrystalline cellulose, colloidal anhydrous silica, povidone, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol (polyethylene glycol), talc, and iron oxide.

Safety and effectiveness of ESBRIET in pediatric patients have not been established.

Of the total number of subjects in the clinical studies receiving ESBRIET, 714 (67%) were 65 years old and over, while 231 (22%) were 75 years old and over. No overall differences in safety or effectiveness were observed between older and younger patients. No dosage adjustment is required based upon age.

The efficacy of ESBRIET was evaluated in patients with IPF in three phase 3, randomized, double-blind, placebo-controlled, multicenter trials (Studies 1, 2, and 3).

Study 1 was a 52-week trial comparing ESBRIET 2403 mg/day (n=278) versus placebo (n=277) in patients with IPF. Study 2 and Study 3 were nearly identical to each other in design, with few exceptions, including an intermediate dose treatment arm in Study 2. Study 2 compared treatment with either ESBRIET 2403 mg/day (n=174) or ESBRIET 1197 mg/day (n=87) to placebo (n=174), while Study 3 compared ESBRIET 2403 mg/day (n=171) to placebo (n=173). Study drug was administered three times daily with food for a minimum of 72 weeks. Patients continued on treatment until the last patient completed 72 weeks of treatment, which included observations to approximately 120 weeks of study treatment. The primary endpoint was the change in percent predicted forced vital capacity (%FVC) from baseline to study end, measured at 52 weeks in Study 1, and at 72 weeks in Studies 2 and 3.

Studies 1, 2 and 3 enrolled adult patients who had a clinical and radiographic diagnosis of IPF (with or without accompanying surgical lung biopsy), without evidence or suspicion of an alternative diagnosis for interstitial lung disease. Eligible patients were to have %FVC greater than or equal to 50% at baseline and a percent predicted diffusing capacity of the lungs for carbon monoxide (%DL _CO) greater than or equal to 30% (Study 1) or 35% (Studies 2 and 3) at baseline. In all three trials, over 80% of patients completed study treatment.

A total of 1247 patients with IPF were randomized to receive ESBRIET 2403 mg/day (n=623) or placebo (n=624) in these three trials. Baseline characteristics were generally balanced across treatment groups. The study population ranged from 40 to 80 years of age (mean age 67 years). Most patients were male (74%), white (95%), and current or former smokers (65%). Approximately 93% of patients met criteria for definite IPF on high resolution computed tomography (HRCT). Baseline mean %FVC and %DL _COwere 72% and 46%, respectively. Approximately 15% subjects discontinued from each treatment group.

None.

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Liver Enzyme Elevations and Drug-Induced Liver Injury [see Warnings and Precautions (5.1)]
• Photosensitivity Reaction or Rash [see Warnings and Precautions (5.2)]
• Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.3)]
• Gastrointestinal Disorders [see Warnings and Precautions (5.4)]

Moderate (e.g., ciprofloxacin) and strong inhibitors of CYP1A2 (e.g., fluvoxamine) increase systemic exposure of ESBRIET and may alter the adverse reaction profile of ESBRIET. Discontinue fluvoxamine prior to administration of ESBRIET or reduce to 267 mg three times a day . Consider dosage reduction with use of ciprofloxacin. ( 7.1)

The concomitant use of ESBRIET and a CYP1A2 inducer may decrease the exposure of ESBRIET and this may lead to loss of efficacy. Therefore, discontinue use of strong CYP1A2 inducers prior to ESBRIET treatment and avoid the concomitant use of ESBRIET and a strong CYP1A2 inducer [see Clinical Pharmacology (12.3)] .

ESBRIET should be used with caution in patients with mild (CL _cr50–80 mL/min), moderate (CL _cr30–50 mL/min), or severe (CL _crless than 30 mL/min) renal impairment [see Clinical Pharmacology (12.3)]. Monitor for adverse reactions and consider dosage modification or discontinuation of ESBRIET as needed [see Dosage and Administration (2.3)] . The safety, efficacy, and pharmacokinetics of ESBRIET have not been studied in patients with end-stage renal disease requiring dialysis. Use of ESBRIET in patients with end-stage renal diseases requiring dialysis is not recommended.

Pirfenidone is metabolized primarily (70 to 80%) via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1.

The recommended daily maintenance dosage of ESBRIET is 801 mg three times daily for a total of 2403 mg/day. Doses should be taken with food at the same time each day.

Upon initiation of treatment, titrate to the full dosage of 2403 mg/day over a 14-day period as follows:

Dosages above 2403 mg/day are not recommended for any patient. Patients should not take 2 doses at the same time to make up for a missed dose. Patients should not take more than 3 doses per day.

ESBRIET should be used with caution in patients with mild (Child Pugh Class A) to moderate (Child Pugh Class B) hepatic impairment. Monitor for adverse reactions and consider dosage modification or discontinuation of ESBRIET as needed [see Dosage and Administration (2.3)] .

The safety, efficacy, and pharmacokinetics of ESBRIET have not been studied in patients with severe hepatic impairment. ESBRIET is not recommended for use in patients with severe (Child Pugh Class C) hepatic impairment [see Clinical Pharmacology (12.3)] .

ESBRIET is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).

The mechanism of action of pirfenidone in the treatment of IPF has not been established.

• Elevated liver enzymes and drug-induced liver injury: ALT, AST, and bilirubin elevations have occurred with ESBRIET including cases of drug-induced liver injury. In the postmarketing setting, non-serious and serious cases of drug-induced liver injury, including severe liver injury with fatal outcomes, have been reported. Monitor ALT, AST, and bilirubin before and during treatment. Temporary dosage reductions or discontinuations may be required. ( 2.1, 5.1)
• Photosensitivity and rash: Photosensitivity and rash have been noted with ESBRIET. Avoid exposure to sunlight and sunlamps. Wear sunscreen and protective clothing daily. Temporary dosage reductions or discontinuations may be required. ( 5.2)
• Severe Cutaneous Adverse Reactions (SCAR): Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS) have been reported in association with the use of ESBRIET in the postmarketing setting. Interrupt ESBRIET in case of signs or symptoms of SCAR. Permanently discontinue ESBRIET if a SCAR is confirmed. ( 5.3)
• Gastrointestinal disorders: Nausea, vomiting, diarrhea, dyspepsia, gastro-esophageal reflux disease, and abdominal pain have occurred with ESBRIET. Temporary dosage reductions or discontinuations may be required. ( 5.4)

• Take with food.
• Recommended dosage: 801 mg three times daily (2403 mg/day). ( 2)
• Upon initiation of treatment, titrate to the full dosage of 2403 mg/day over a 14-day period as follows:

• Consider temporary dosage reduction, treatment interruption, or discontinuation for management of adverse reactions. ( 2.3, 5.1, 5.2, 5.3, 5.4)
• Prior to treatment, conduct liver function tests. ( 2.1)

Film-coated tablets: oval, biconvex, debossed with "PFD", containing 267 mg (yellow) and 801 mg (brown) pirfenidone

In addition to adverse reactions identified from clinical trials the following adverse reactions have been identified during post-approval use of ESBRIET. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

Blood and Lymphatic System Disorders:Agranulocytosis

Hepatobiliary Disorders:Drug-induced liver injury

Immune System Disorders:Angioedema

Skin and Subcutaneous Tissue Disorders:Severe Cutaneous Adverse Reactions (SCAR)

• Hepatic Impairment: Monitor for adverse reactions and consider dosage modification or discontinuation of ESBRIET as needed. ESBRIET is not recommended for use in patients with severe hepatic impairment. ( 8.6, 12.3)
• Renal Impairment: Monitor for adverse reactions and consider dosage modification or discontinuation of ESBRIET as needed. ESBRIET is not recommended for use in patients with end stage renal disease on dialysis. ( 8.7, 12.3)
• Smokers: Decreased exposure has been noted in smokers which may alter the efficacy profile of ESBRIET. ( 8.8)

In the clinical studies, gastrointestinal events of nausea, diarrhea, dyspepsia, vomiting, gastro-esophageal reflux disease, and abdominal pain were more frequently reported by patients in the ESBRIET treatment groups than in those taking placebo. Dosage reduction or interruption for gastrointestinal events was required in 18.5% of patients in the 2403 mg/day group, as compared to 5.8% of patients in the placebo group; 2.2% of patients in the ESBRIET 2403 mg/day group discontinued treatment due to a gastrointestinal event, as compared to 1.0% in the placebo group. The most common (>2%) gastrointestinal events that led to dosage reduction or interruption were nausea, diarrhea, vomiting, and dyspepsia. The incidence of gastrointestinal events was highest early in the course of treatment (with highest incidence occurring during the initial 3 months) and decreased over time. Dosage modifications may be necessary in some cases of gastrointestinal adverse reactions [see Dosage and Administration (2.3)] .

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of pirfenidone has been evaluated in more than 1400 subjects with over 170 subjects exposed to pirfenidone for more than 5 years in clinical trials.

ESBRIET was studied in 3 randomized, double-blind, placebo-controlled trials (Studies 1, 2, and 3) in which a total of 623 patients received 2403 mg/day of ESBRIET and 624 patients received placebo. Subjects ages ranged from 40 to 80 years (mean age of 67 years). Most patients were male (74%) and Caucasian (95%). The mean duration of exposure to ESBRIET was 62 weeks (range: 2 to 118 weeks) in these 3 trials.

At the recommended dosage of 2403 mg/day, 14.6% of patients on ESBRIET compared to 9.6% on placebo permanently discontinued treatment because of an adverse event. The most common (>1%) adverse reactions leading to discontinuation were rash and nausea. The most common (>3%) adverse reactions leading to dosage reduction or interruption were rash, nausea, diarrhea, and photosensitivity reaction.

The most common adverse reactions with an incidence of ≥10% and more frequent in the ESBRIET than placebo treatment group are listed in Table 2.

Adverse reactions occurring in ≥5 to <10% of ESBRIET-treated patients and more commonly than placebo are photosensitivity reaction (9% vs. 1%), pruritus (8% vs. 5%), asthenia (6% vs. 4%), dysgeusia (6% vs. 2%), and non-cardiac chest pain (5% vs. 4%).

Advise the patient to read the FDA-approved patient labeling ( Patient Information).

ESBRIET film-coated tablets are oval, biconvex, debossed with "PFD", containing 267 mg (yellow) and 801 mg (brown) pirfenidone. The film-coated tablets are supplied in bottles.

ESBRIET film-coated tablets:

• NDC 83107-028-27, carton containing 1 bottle containing 270 tablets, 267 mg each, with a child-resistant closure
• NDC 83107-029-90, carton containing 1 bottle containing 90 tablets, 801 mg each, with a child-resistant closure

Patients treated with ESBRIET 2403 mg/day in the three Phase 3 studies had a higher incidence of photosensitivity reactions (9%) compared with patients treated with placebo (1%). The majority of the photosensitivity reactions occurred during the initial 6 months. Instruct patients to avoid or minimize exposure to sunlight (including sunlamps), to use a sunblock (SPF 50 or higher), and to wear clothing that protects against sun exposure. Additionally, instruct patients to avoid concomitant medications known to cause photosensitivity. Dosage reduction or discontinuation may be necessary in some cases of photosensitivity reaction or rash [see Dosage and Administration (2.3)] .

Severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported in association with the use of ESBRIET in the postmarketing setting. If signs or symptoms of SCAR occur, interrupt ESBRIET treatment until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, permanently discontinue ESBRIET.

Conduct liver function tests prior to initiating treatment with ESBRIET [see Warnings and Precautions (5.1)].

Patients who miss 14 or more days of ESBRIET should re-initiate treatment by undergoing the initial 2-week titration regimen up to the full maintenance dosage [see Dosage and Administration (2.2)] . For treatment interruption of less than 14 days, the dosage prior to the interruption can be resumed.

If patients experience significant adverse reactions (i.e., gastrointestinal, photosensitivity reaction or rash, severe cutaneous adverse reactions (SCAR)), consider temporary dosage reductions or interruptions of ESBRIET to allow for resolution of symptoms. If a SCAR is confirmed, permanently discontinue ESBRIET [see Warnings and Precautions (5.1, 5.2, 5.3, 5.4)] .

Cases of drug-induced liver injury (DILI) have been observed with ESBRIET. In the postmarketing period, non-serious and serious cases of DILI, including severe liver injury with fatal outcome, have been reported. Patients treated with Esbriet 2403 mg/day in three Phase 3 trials had a higher incidence of elevations in ALT or AST ≥3× ULN than placebo patients (3.7% vs 0.8%, respectively). Elevations ≥10×ULN in ALT or AST occurred in 0.3% of patients in the Esbriet 2403 mg/day group and in 0.2% of patients in the placebo group. Increases in ALT and AST ≥3× ULN were reversible with dose modification or treatment discontinuation.

Conduct liver function tests (ALT, AST, and bilirubin) prior to the initiation of therapy with ESBRIET, monthly for the first 6 months, every 3 months thereafter, and as clinically indicated. 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 modification or interruption may be necessary for liver enzyme elevations [see Dosage and Administration (2.1, 2.3)] .

Dosage Modification due to Elevated Liver Enzymes

Dosage modifications or interruptions may also be necessary when liver enzyme and bilirubin elevations are exhibited. For liver enzyme elevations, modify the dosage as follows:

If a patient exhibits >3 but ≤5 × the upper limit of normal (ULN) ALT and/or AST without symptoms or hyperbilirubinemia after starting ESBRIET therapy:

• Discontinue confounding medications, exclude other causes, and monitor the patient closely.
• Repeat liver chemistry tests as clinically indicated.
• The full daily dosage may be maintained, if clinically appropriate, or reduced or interrupted (e.g., until liver chemistry tests are within normal limits) with subsequent re-titration to the full dosage as tolerated.

If a patient exhibits >3 but ≤5 × ULN ALT and/or AST accompanied by symptoms or hyperbilirubinemia:

• Permanently discontinue ESBRIET.
• Do not rechallenge patient with ESBRIET.

If a patient exhibits >5 × ULN ALT and/or AST:

• Permanently discontinue ESBRIET.
• Do not rechallenge patient with ESBRIET.

Representative sample of labeling (see the HOW SUPPLIEDsection for complete listing):

Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) (see USP Controlled Room Temperature).

Keep the bottle tightly closed. Do not use if the seal over the bottle opening is broken or missing. Safely throw away any ESBRIET that is out of date or no longer needed.

Smoking causes decreased exposure to ESBRIET [see Clinical Pharmacology (12.3)], which may alter the efficacy profile of ESBRIET. Instruct patients to stop smoking prior to treatment with ESBRIET and to avoid smoking when using ESBRIET.

There is limited clinical experience with overdosage. Multiple dosages of ESBRIET up to a maximum tolerated dose of 4005 mg per day were administered as five 267 mg capsules three times daily to healthy adult volunteers over a 12-day dose escalation.

In the event of a suspected overdosage, appropriate supportive medical care should be provided, including monitoring of vital signs and observation of the clinical status of the patient.

ESBRIET belongs to the chemical class of pyridone. ESBRIET is available as a white to off-white hard gelatin capsule containing 267 mg of pirfenidone for oral administration, or, as film-coated tablets containing 267 mg (yellow) and 801 mg (brown) pirfenidone.

Pirfenidone has a molecular formula of C ₁₂H ₁₁NO and a molecular weight of 185.23. Pirfenidone has the following structural formula, which has been referred to as 5-methyl-1-phenyl-2-1(H)-pyridone or 5-methyl-1-phenyl-2-(1H)-pyridone.

Pirfenidone is a white to pale yellow, non-hygroscopic powder. It is more soluble in methanol, ethyl alcohol, acetone and chloroform than in water and 1.0 N HCl. The melting point is approximately 109°C.

ESBRIET capsule contains pirfenidone and the following inactive ingredients: microcrystalline cellulose, croscarmellose sodium, povidone, and magnesium stearate.

In addition, the capsule shell contains gelatin and titanium dioxide. The capsule brown printing ink includes shellac, iron oxide black, iron oxide red, iron oxide yellow, propylene glycol, ammonium hydroxide.

ESBRIET tablets contain pirfenidone and the following inactive ingredients: Microcrystalline cellulose, colloidal anhydrous silica, povidone, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol (polyethylene glycol), talc, and iron oxide.

Safety and effectiveness of ESBRIET in pediatric patients have not been established.

Of the total number of subjects in the clinical studies receiving ESBRIET, 714 (67%) were 65 years old and over, while 231 (22%) were 75 years old and over. No overall differences in safety or effectiveness were observed between older and younger patients. No dosage adjustment is required based upon age.

The efficacy of ESBRIET was evaluated in patients with IPF in three phase 3, randomized, double-blind, placebo-controlled, multicenter trials (Studies 1, 2, and 3).

Study 1 was a 52-week trial comparing ESBRIET 2403 mg/day (n=278) versus placebo (n=277) in patients with IPF. Study 2 and Study 3 were nearly identical to each other in design, with few exceptions, including an intermediate dose treatment arm in Study 2. Study 2 compared treatment with either ESBRIET 2403 mg/day (n=174) or ESBRIET 1197 mg/day (n=87) to placebo (n=174), while Study 3 compared ESBRIET 2403 mg/day (n=171) to placebo (n=173). Study drug was administered three times daily with food for a minimum of 72 weeks. Patients continued on treatment until the last patient completed 72 weeks of treatment, which included observations to approximately 120 weeks of study treatment. The primary endpoint was the change in percent predicted forced vital capacity (%FVC) from baseline to study end, measured at 52 weeks in Study 1, and at 72 weeks in Studies 2 and 3.

Studies 1, 2 and 3 enrolled adult patients who had a clinical and radiographic diagnosis of IPF (with or without accompanying surgical lung biopsy), without evidence or suspicion of an alternative diagnosis for interstitial lung disease. Eligible patients were to have %FVC greater than or equal to 50% at baseline and a percent predicted diffusing capacity of the lungs for carbon monoxide (%DL _CO) greater than or equal to 30% (Study 1) or 35% (Studies 2 and 3) at baseline. In all three trials, over 80% of patients completed study treatment.

A total of 1247 patients with IPF were randomized to receive ESBRIET 2403 mg/day (n=623) or placebo (n=624) in these three trials. Baseline characteristics were generally balanced across treatment groups. The study population ranged from 40 to 80 years of age (mean age 67 years). Most patients were male (74%), white (95%), and current or former smokers (65%). Approximately 93% of patients met criteria for definite IPF on high resolution computed tomography (HRCT). Baseline mean %FVC and %DL _COwere 72% and 46%, respectively. Approximately 15% subjects discontinued from each treatment group.

None.

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Liver Enzyme Elevations and Drug-Induced Liver Injury [see Warnings and Precautions (5.1)]
• Photosensitivity Reaction or Rash [see Warnings and Precautions (5.2)]
• Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.3)]
• Gastrointestinal Disorders [see Warnings and Precautions (5.4)]

Moderate (e.g., ciprofloxacin) and strong inhibitors of CYP1A2 (e.g., fluvoxamine) increase systemic exposure of ESBRIET and may alter the adverse reaction profile of ESBRIET. Discontinue fluvoxamine prior to administration of ESBRIET or reduce to 267 mg three times a day . Consider dosage reduction with use of ciprofloxacin. ( 7.1)

The concomitant use of ESBRIET and a CYP1A2 inducer may decrease the exposure of ESBRIET and this may lead to loss of efficacy. Therefore, discontinue use of strong CYP1A2 inducers prior to ESBRIET treatment and avoid the concomitant use of ESBRIET and a strong CYP1A2 inducer [see Clinical Pharmacology (12.3)] .

ESBRIET should be used with caution in patients with mild (CL _cr50–80 mL/min), moderate (CL _cr30–50 mL/min), or severe (CL _crless than 30 mL/min) renal impairment [see Clinical Pharmacology (12.3)]. Monitor for adverse reactions and consider dosage modification or discontinuation of ESBRIET as needed [see Dosage and Administration (2.3)] . The safety, efficacy, and pharmacokinetics of ESBRIET have not been studied in patients with end-stage renal disease requiring dialysis. Use of ESBRIET in patients with end-stage renal diseases requiring dialysis is not recommended.

Pirfenidone is metabolized primarily (70 to 80%) via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1.

The recommended daily maintenance dosage of ESBRIET is 801 mg three times daily for a total of 2403 mg/day. Doses should be taken with food at the same time each day.

Upon initiation of treatment, titrate to the full dosage of 2403 mg/day over a 14-day period as follows:

Dosages above 2403 mg/day are not recommended for any patient. Patients should not take 2 doses at the same time to make up for a missed dose. Patients should not take more than 3 doses per day.

ESBRIET should be used with caution in patients with mild (Child Pugh Class A) to moderate (Child Pugh Class B) hepatic impairment. Monitor for adverse reactions and consider dosage modification or discontinuation of ESBRIET as needed [see Dosage and Administration (2.3)] .

The safety, efficacy, and pharmacokinetics of ESBRIET have not been studied in patients with severe hepatic impairment. ESBRIET is not recommended for use in patients with severe (Child Pugh Class C) hepatic impairment [see Clinical Pharmacology (12.3)] .

ESBRIET is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).

The mechanism of action of pirfenidone in the treatment of IPF has not been established.

• Elevated liver enzymes and drug-induced liver injury: ALT, AST, and bilirubin elevations have occurred with ESBRIET including cases of drug-induced liver injury. In the postmarketing setting, non-serious and serious cases of drug-induced liver injury, including severe liver injury with fatal outcomes, have been reported. Monitor ALT, AST, and bilirubin before and during treatment. Temporary dosage reductions or discontinuations may be required. ( 2.1, 5.1)
• Photosensitivity and rash: Photosensitivity and rash have been noted with ESBRIET. Avoid exposure to sunlight and sunlamps. Wear sunscreen and protective clothing daily. Temporary dosage reductions or discontinuations may be required. ( 5.2)
• Severe Cutaneous Adverse Reactions (SCAR): Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS) have been reported in association with the use of ESBRIET in the postmarketing setting. Interrupt ESBRIET in case of signs or symptoms of SCAR. Permanently discontinue ESBRIET if a SCAR is confirmed. ( 5.3)
• Gastrointestinal disorders: Nausea, vomiting, diarrhea, dyspepsia, gastro-esophageal reflux disease, and abdominal pain have occurred with ESBRIET. Temporary dosage reductions or discontinuations may be required. ( 5.4)

• Take with food.
• Recommended dosage: 801 mg three times daily (2403 mg/day). ( 2)
• Upon initiation of treatment, titrate to the full dosage of 2403 mg/day over a 14-day period as follows:

• Consider temporary dosage reduction, treatment interruption, or discontinuation for management of adverse reactions. ( 2.3, 5.1, 5.2, 5.3, 5.4)
• Prior to treatment, conduct liver function tests. ( 2.1)

Film-coated tablets: oval, biconvex, debossed with "PFD", containing 267 mg (yellow) and 801 mg (brown) pirfenidone

In addition to adverse reactions identified from clinical trials the following adverse reactions have been identified during post-approval use of ESBRIET. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

Blood and Lymphatic System Disorders:Agranulocytosis

Hepatobiliary Disorders:Drug-induced liver injury

Immune System Disorders:Angioedema

Skin and Subcutaneous Tissue Disorders:Severe Cutaneous Adverse Reactions (SCAR)

• Hepatic Impairment: Monitor for adverse reactions and consider dosage modification or discontinuation of ESBRIET as needed. ESBRIET is not recommended for use in patients with severe hepatic impairment. ( 8.6, 12.3)
• Renal Impairment: Monitor for adverse reactions and consider dosage modification or discontinuation of ESBRIET as needed. ESBRIET is not recommended for use in patients with end stage renal disease on dialysis. ( 8.7, 12.3)
• Smokers: Decreased exposure has been noted in smokers which may alter the efficacy profile of ESBRIET. ( 8.8)

In the clinical studies, gastrointestinal events of nausea, diarrhea, dyspepsia, vomiting, gastro-esophageal reflux disease, and abdominal pain were more frequently reported by patients in the ESBRIET treatment groups than in those taking placebo. Dosage reduction or interruption for gastrointestinal events was required in 18.5% of patients in the 2403 mg/day group, as compared to 5.8% of patients in the placebo group; 2.2% of patients in the ESBRIET 2403 mg/day group discontinued treatment due to a gastrointestinal event, as compared to 1.0% in the placebo group. The most common (>2%) gastrointestinal events that led to dosage reduction or interruption were nausea, diarrhea, vomiting, and dyspepsia. The incidence of gastrointestinal events was highest early in the course of treatment (with highest incidence occurring during the initial 3 months) and decreased over time. Dosage modifications may be necessary in some cases of gastrointestinal adverse reactions [see Dosage and Administration (2.3)] .

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of pirfenidone has been evaluated in more than 1400 subjects with over 170 subjects exposed to pirfenidone for more than 5 years in clinical trials.

ESBRIET was studied in 3 randomized, double-blind, placebo-controlled trials (Studies 1, 2, and 3) in which a total of 623 patients received 2403 mg/day of ESBRIET and 624 patients received placebo. Subjects ages ranged from 40 to 80 years (mean age of 67 years). Most patients were male (74%) and Caucasian (95%). The mean duration of exposure to ESBRIET was 62 weeks (range: 2 to 118 weeks) in these 3 trials.

At the recommended dosage of 2403 mg/day, 14.6% of patients on ESBRIET compared to 9.6% on placebo permanently discontinued treatment because of an adverse event. The most common (>1%) adverse reactions leading to discontinuation were rash and nausea. The most common (>3%) adverse reactions leading to dosage reduction or interruption were rash, nausea, diarrhea, and photosensitivity reaction.

The most common adverse reactions with an incidence of ≥10% and more frequent in the ESBRIET than placebo treatment group are listed in Table 2.

Adverse reactions occurring in ≥5 to <10% of ESBRIET-treated patients and more commonly than placebo are photosensitivity reaction (9% vs. 1%), pruritus (8% vs. 5%), asthenia (6% vs. 4%), dysgeusia (6% vs. 2%), and non-cardiac chest pain (5% vs. 4%).

Advise the patient to read the FDA-approved patient labeling ( Patient Information).

ESBRIET film-coated tablets are oval, biconvex, debossed with "PFD", containing 267 mg (yellow) and 801 mg (brown) pirfenidone. The film-coated tablets are supplied in bottles.

ESBRIET film-coated tablets:

• NDC 83107-028-27, carton containing 1 bottle containing 270 tablets, 267 mg each, with a child-resistant closure
• NDC 83107-029-90, carton containing 1 bottle containing 90 tablets, 801 mg each, with a child-resistant closure

Patients treated with ESBRIET 2403 mg/day in the three Phase 3 studies had a higher incidence of photosensitivity reactions (9%) compared with patients treated with placebo (1%). The majority of the photosensitivity reactions occurred during the initial 6 months. Instruct patients to avoid or minimize exposure to sunlight (including sunlamps), to use a sunblock (SPF 50 or higher), and to wear clothing that protects against sun exposure. Additionally, instruct patients to avoid concomitant medications known to cause photosensitivity. Dosage reduction or discontinuation may be necessary in some cases of photosensitivity reaction or rash [see Dosage and Administration (2.3)] .

Severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported in association with the use of ESBRIET in the postmarketing setting. If signs or symptoms of SCAR occur, interrupt ESBRIET treatment until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, permanently discontinue ESBRIET.

Conduct liver function tests prior to initiating treatment with ESBRIET [see Warnings and Precautions (5.1)].

Patients who miss 14 or more days of ESBRIET should re-initiate treatment by undergoing the initial 2-week titration regimen up to the full maintenance dosage [see Dosage and Administration (2.2)] . For treatment interruption of less than 14 days, the dosage prior to the interruption can be resumed.

If patients experience significant adverse reactions (i.e., gastrointestinal, photosensitivity reaction or rash, severe cutaneous adverse reactions (SCAR)), consider temporary dosage reductions or interruptions of ESBRIET to allow for resolution of symptoms. If a SCAR is confirmed, permanently discontinue ESBRIET [see Warnings and Precautions (5.1, 5.2, 5.3, 5.4)] .

Cases of drug-induced liver injury (DILI) have been observed with ESBRIET. In the postmarketing period, non-serious and serious cases of DILI, including severe liver injury with fatal outcome, have been reported. Patients treated with Esbriet 2403 mg/day in three Phase 3 trials had a higher incidence of elevations in ALT or AST ≥3× ULN than placebo patients (3.7% vs 0.8%, respectively). Elevations ≥10×ULN in ALT or AST occurred in 0.3% of patients in the Esbriet 2403 mg/day group and in 0.2% of patients in the placebo group. Increases in ALT and AST ≥3× ULN were reversible with dose modification or treatment discontinuation.

Conduct liver function tests (ALT, AST, and bilirubin) prior to the initiation of therapy with ESBRIET, monthly for the first 6 months, every 3 months thereafter, and as clinically indicated. 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 modification or interruption may be necessary for liver enzyme elevations [see Dosage and Administration (2.1, 2.3)] .