Prescription Drugs

SIDE EFFECTS The following adverse reactions are discussed in greater detail in other sections of the labeling: Liver Enzyme Elevations [see WARNINGS AND PRECAUTIONS] Photosensitivity Reaction or Rash [see WARNINGS AND PRECAUTIONS] Gastrointestinal Disorders [see WARNINGS AND PRECAUTIONS] Clinical Trials Experience 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. Table 2: Adverse Reactions Occurring in ≥ 10% of ESBRIET-Treated Patients and More Commonly Than Placebo in Studies 1, 2, and 3 Adverse Reaction % of Patients (0 to 118 Weeks) ESBRIET 2403 mg/day (N = 623) Placebo (N = 624) Nausea 36% 16% Rash 30% 10% Abdominal Pain1 24% 15% Upper Respiratory Tract Infection 27% 25% Diarrhea 26% 20% Fatigue 26% 19% Headache 22% 19% Dyspepsia 19% 7% Dizziness 18% 11% Vomiting 13% 6% Anorexia 13% 5% Gastro-esophageal Reflux Disease 11% 7% Sinusitis 11% 10% Insomnia 10% 7% Weight Decreased 10% 5% Arthralgia 10% 7% 1 Includes abdominal pain, upper abdominal pain, abdominal distension, and stomach discomfort. Adverse reactions occurring in ≥ 5 to < 10% of ESBRIET-treated patients and more commonly than placebo are photosensitivity reaction (9% vs. 1%), decreased appetite (8% vs. 3%), pruritus (8% vs. 5%), asthenia (6% vs. 4%), dysgeusia (6% vs. 2%), and non-cardiac chest pain (5% vs. 4%). Postmarketing Experience In addition to adverse reactions identified from clinical trials the following adverse reactions have been identified during post-approval use of pirfenidone. 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 Immune System Disorders Angioedema Hepatobiliary Disorders Bilirubin increased in combination with increases of ALT and AST DRUG INTERACTIONS CYP1A2 Inhibitors Pirfenidone is metabolized primarily (70 to 80%) via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1. Strong CYP1A2 Inhibitors The concomitant administration of ESBRIET and fluvoxamine or other strong CYP1A2 inhibitors (e.g., enoxacin) is not recommended because it significantly increases exposure to ESBRIET [see CLINICAL PHARMACOLOGY]. Use of fluvoxamine or other strong CYP1A2 inhibitors should be discontinued prior to administration of ESBRIET and avoided during ESBRIET treatment. In the event that fluvoxamine or other strong CYP1A2 inhibitors are the only drug of choice, dosage reductions are recommended. Monitor for adverse reactions and consider discontinuation of ESBRIET as needed [see DOSAGE AND ADMINISTRATION]. Moderate CYP1A2 Inhibitors Concomitant administration of ESBRIET and ciprofloxacin (a moderate inhibitor of CYP1A2) moderately increases exposure to ESBRIET [see CLINICAL PHARMACOLOGY]. If ciprofloxacin at the dosage of 750 mg twice daily cannot be avoided, dosage reductions are recommended [see DOSAGE AND ADMINISTRATION]. Monitor patients closely when ciprofloxacin is used at a dosage of 250 mg or 500 mg once daily. Concomitant CYP1A2 And Other CYP Inhibitors Agents or combinations of agents that are moderate or strong inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of ESBRIET (i.e., CYP2C9, 2C19, 2D6, and 2E1) should be discontinued prior to and avoided during ESBRIET treatment. CYP1A2 Inducers 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].

Find Lowest Prices on ESBRIET® (pirfenidone) Capsules DESCRIPTION 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 C12H11NO and a molecular weight of 185.23. Pirfenidone has the following structural formula, which has been referred to as 5-methyl-1phenyl-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.

INDICATIONS ESBRIET is indicated for the treatment of idiopathic pulmonary fibrosis (IPF). DOSAGE AND ADMINISTRATION Testing Prior To ESBRIET Administration Conduct liver function tests prior to initiating treatment with ESBRIET [see WARNINGS AND PRECAUTIONS]. Recommended Dosage 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: Table 1: Dosage Titration for ESBRIET in Patients with IPF Treatment days Dosage Days 1 through 7 267 mg three times daily (801 mg/day) Days 8 through 14 534 mg three times daily (1602 mg/day) Days 15 onward 801 mg three times daily (2403 mg/day) 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. Dosage Modifications Due To Adverse Reactions 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 Recommended Dosage]. 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), consider temporary dosage reductions or interruptions of ESBRIET to allow for resolution of symptoms [see WARNINGS AND PRECAUTIONS]. 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 x 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 retitration to the full dosage as tolerated. If a patient exhibits > 3 but ≥ 5 x ULN ALT and/or AST accompanied by symptoms or hyperbilirubinemia: Permanently discontinue ESBRIET. Do not rechallenge patient with ESBRIET. If a patient exhibits > 5 x ULN ALT and/or AST: Permanently discontinue ESBRIET. Do not rechallenge patient with ESBRIET. Dosage Modification Due To Drug Interactions Strong CYP1A2 Inhibitors (e.g., fluvoxamine, enoxacin) Reduce ESBRIET to 267 mg three times a day (801 mg/day). Moderate CYP1A2 Inhibitors (e.g., ciprofloxacin) With use of ciprofloxacin at a dosage of 750 mg twice daily, reduce ESBRIET to 534 mg three times a day (1602 mg/day). HOW SUPPLIED Dosage Forms And Strengths Capsules: 267 mg, white to off-white, hard gelatin capsules printed with “PFD 267 mg” on the cap of the capsule in brown ink. Film-coated tablets: oval, biconvex, debossed with “PFD”, containing 267 mg (yellow) and 801 mg (brown) pirfenidone Storage And Handling ESBRIET white to off-white hard gelatin capsules contain 267 mg of pirfenidone. The cap of the capsule is printed with “PFD 267 mg” in brown ink. The capsule is supplied either in a bottle, a 14-day titration blister pack or a 4-week maintenance blister pack. 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 Capsules NDC 50242-121-01, bottle for a 30-day supply containing 270 capsules and closed with a child-resistant closure NDC 50242-121-02, 14-day titration blister pack, carton containing a total of 63 capsules in two blister cards - a Week 1 blister card containing 21 capsules (1 capsule per blister well) and a Week 2 blister card containing 42 capsules (2 capsules per blister well) NDC 50242-121-03, 4-week maintenance blister pack, carton containing a total of 252 capsules in four blister cards each with 63 capsules (3 capsules per blister well) ESBRIET Film-coated Tablets NDC 50242-122-05, carton containing 3 bottles, each containing ninety 267 mg tablets (270 tablets total) with a child-resistant closure NDC 50242-123-01, carton containing 1 bottle containing ninety 801 mg tablets, with a child-resistant closure 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. Distributed by: Genentech USA, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990. Revised: Jan2017

PATIENT INFORMATION ESBRIET (es-BREE-et) (pirfenidone) Capsules and Film-coated Tablets What is ESBRIET? ESBRIET is a prescription medicine used to treat people with a lung disease called idiopathic pulmonary fibrosis (IPF). It is not known if ESBRIET is safe and effective in children. Before you take ESBRIET, tell your doctor about all of your medical conditions, including if you: have liver problems have kidney problems are a smoker are pregnant or plan to become pregnant. It is not known if ESBRIET will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if ESBRIET passes into your breast milk. You and your doctor should decide if you will take ESBRIET. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should I take ESBRIET? Take ESBRIET exactly as your doctor tells you to take it. Your doctor may change your dose of ESBRIET as needed. Take ESBRIET with food at the same time each day. This may help to decrease your nausea and dizziness. ESBRIET 267 mg is supplied as either a white to off-white capsule or a yellow tablet. If you have been prescribed ESBRIET 267 mg, take it as follows: Take 1 ESBRIET 267 mg capsule or tablet 3 times each day for days 1 through 7. Take 2 ESBRIET 267 mg capsule or tablet 3 times each day for days 8 through 14. Take 3 ESBRIET 267 mg capsule or tablet 3 times each day on day 15 and each day after. Week Morning (Breakfast) Afternoon (Lunch) Evening (Dinner) Total Pills Each Day Days 1-7 1 1 1 3 Days 8-14 2 2 2 6 Days 15 onward 3 3 3 9 If you have been prescribed the brown 801 mg ESBRIET film-coated tablets, take it as follows: Take 1 brown 801 mg ESBRIET tablet 3 times each day. Week Morning (Breakfast) Afternoon (Lunch) Evening (Dinner) Total Pills Each Day Days 15 onward 1 1 1 3 If you miss 14 days or more of ESBRIET call your doctor right away for further instructions about how to take your medicine. Do not take 2 doses at the same time to make up for your missed dose. Do not take more than 3 doses each day. If you take too much ESBRIET, call your doctor or go to the nearest hospital emergency room right away. Your doctor should do certain blood tests before you start taking ESBRIET. What should I avoid while taking ESBRIET? Avoid sunlight. ESBRIET can make your skin sensitive to the sun and the light from sunlamps and tanning beds. You could get a severe sunburn. Use sunscreen (SPF 50) and wear a hat and clothes that cover your skin if you have to be in sunlight. Talk to your doctor if you get sunburn or a rash. Avoid taking ESBRIET with other medicines that can make your skin sensitive to the sun, the light from sunlamps and tanning beds. Avoid smoking. Smoking may affect how well ESBRIET works. What are the possible side effects of ESBRIET? ESBRIET may cause serious side effects, including: liver problems. Call your doctor right away if you have unexplained symptoms such as yellowing of your skin or the white part of your eyes (jaundice), dark or brown (tea colored) urine, pain on the upper right side of your stomach area (abdomen), bleeding or bruising more easily than normal, feeling tired. Your doctor will do blood tests to check how your liver is working during your treatment with ESBRIET. sensitivity to sunlight (photosensitivity) and rash. See “What should I avoid while taking ESBRIET?” stomach problems. ESBRIET may cause stomach problems such as nausea, vomiting, diarrhea, indigestion, heartburn, and stomach pain. Tell your doctor right away if your stomach problems get worse or do not go away. Your doctor may need to change your dose of ESBRIET. The most common side effects of ESBRIET include feeling tired, insomnia, upper respiratory tract infections, sinusitis, headache, dizziness, decreased weight and decreased or loss of appetite. These are not all the possible side effects of ESBRIET. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store ESBRIET? Store ESBRIET capsules and tablets at room temperature, 77°F (25°C). Keep in a tightly closed container. Safely throw away any ESBRIET that is out of date or no longer needed. Keep ESBRIET and all medicines out of reach of children. General information about the safe and effective use of ESBRIET. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ESBRIET for a condition for which it was not prescribed. Do not give ESBRIET to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or doctor for information about ESBRIET that is written for health professionals. What are the ingredients in ESBRIET capsules? Active ingredient: pirfenidone Inactive ingredients: microcrystalline cellulose, croscarmellose sodium, povidone, and magnesium stearate Capsule Shell: gelatin and titanium dioxide Capsule Brown Printing Ink: shellac, iron oxide black, iron oxide red, iron oxide yellow, propylene glycol, ammonium hydroxide What are the ingredients in ESBRIET film-coated tablets? Active ingredient: pirfenidone Inactive ingredients: microcrystalline cellulose, colloidal anhydrous silica, povidone, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol (polyethylene glycol), talc, and iron oxide For more information, go to www.ESBRIET.com or call 1-888-835-2555.

OVERDOSE 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. CONTRAINDICATIONS None.

SIDE EFFECTS The following adverse reactions are discussed in greater detail in other sections of the labeling: Liver Enzyme Elevations [see WARNINGS AND PRECAUTIONS] Photosensitivity Reaction or Rash [see WARNINGS AND PRECAUTIONS] Gastrointestinal Disorders [see WARNINGS AND PRECAUTIONS] Clinical Trials Experience 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. Table 2: Adverse Reactions Occurring in ≥ 10% of ESBRIET-Treated Patients and More Commonly Than Placebo in Studies 1, 2, and 3 Adverse Reaction % of Patients (0 to 118 Weeks) ESBRIET 2403 mg/day (N = 623) Placebo (N = 624) Nausea 36% 16% Rash 30% 10% Abdominal Pain1 24% 15% Upper Respiratory Tract Infection 27% 25% Diarrhea 26% 20% Fatigue 26% 19% Headache 22% 19% Dyspepsia 19% 7% Dizziness 18% 11% Vomiting 13% 6% Anorexia 13% 5% Gastro-esophageal Reflux Disease 11% 7% Sinusitis 11% 10% Insomnia 10% 7% Weight Decreased 10% 5% Arthralgia 10% 7% 1 Includes abdominal pain, upper abdominal pain, abdominal distension, and stomach discomfort. Adverse reactions occurring in ≥ 5 to < 10% of ESBRIET-treated patients and more commonly than placebo are photosensitivity reaction (9% vs. 1%), decreased appetite (8% vs. 3%), pruritus (8% vs. 5%), asthenia (6% vs. 4%), dysgeusia (6% vs. 2%), and non-cardiac chest pain (5% vs. 4%). Postmarketing Experience In addition to adverse reactions identified from clinical trials the following adverse reactions have been identified during post-approval use of pirfenidone. 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 Immune System Disorders Angioedema Hepatobiliary Disorders Bilirubin increased in combination with increases of ALT and AST DRUG INTERACTIONS CYP1A2 Inhibitors Pirfenidone is metabolized primarily (70 to 80%) via CYP1A2 with minor contributions from other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1. Strong CYP1A2 Inhibitors The concomitant administration of ESBRIET and fluvoxamine or other strong CYP1A2 inhibitors (e.g., enoxacin) is not recommended because it significantly increases exposure to ESBRIET [see CLINICAL PHARMACOLOGY]. Use of fluvoxamine or other strong CYP1A2 inhibitors should be discontinued prior to administration of ESBRIET and avoided during ESBRIET treatment. In the event that fluvoxamine or other strong CYP1A2 inhibitors are the only drug of choice, dosage reductions are recommended. Monitor for adverse reactions and consider discontinuation of ESBRIET as needed [see DOSAGE AND ADMINISTRATION]. Moderate CYP1A2 Inhibitors Concomitant administration of ESBRIET and ciprofloxacin (a moderate inhibitor of CYP1A2) moderately increases exposure to ESBRIET [see CLINICAL PHARMACOLOGY]. If ciprofloxacin at the dosage of 750 mg twice daily cannot be avoided, dosage reductions are recommended [see DOSAGE AND ADMINISTRATION]. Monitor patients closely when ciprofloxacin is used at a dosage of 250 mg or 500 mg once daily. Concomitant CYP1A2 And Other CYP Inhibitors Agents or combinations of agents that are moderate or strong inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved in the metabolism of ESBRIET (i.e., CYP2C9, 2C19, 2D6, and 2E1) should be discontinued prior to and avoided during ESBRIET treatment. CYP1A2 Inducers 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].

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Elevated Liver Enzymes Increases in ALT and AST > 3 x ULN have been reported in patients treated with ESBRIET. In some cases these have been associated with concomitant elevations in bilirubin. Patients treated with ESBRIET 2403 mg/day in the three Phase 3 trials had a higher incidence of elevations in ALT or AST ≥ 3 x ULN than placebo patients (3.7% vs. 0.8%, respectively). Elevations ≥ 10 x 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 x ULN were reversible with dose modification or treatment discontinuation. No cases of liver transplant or death due to liver failure that were related to ESBRIET have been reported. However, the combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury, that could lead to death or the need for liver transplants in some patients. Conduct liver function tests (ALT, AST, and bilirubin) prior to the initiation of therapy with ESBRIET in all patients, then monthly for the first 6 months and every 3 months thereafter. Dosage modifications or interruption may be necessary for liver enzyme elevations [see DOSAGE AND ADMINISTRATION]. Photosensitivity Reaction Or Rash 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]. Gastrointestinal Disorders 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]. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION). Liver Enzyme Elevations Advise patients that they may be required to undergo liver function testing periodically. Instruct patients to immediately report any symptoms of a liver problem (e.g., skin or the white of eyes turn yellow, urine turns dark or brown [tea colored], pain on the right side of stomach, bleed or bruise more easily than normal, lethargy) [see WARNINGS AND PRECAUTIONS]. Photosensitivity Reaction Or Rash Advise patients to avoid or minimize exposure to sunlight (including sunlamps) during use of ESBRIET because of concern for photosensitivity reactions or rash. Instruct patients to use a sunblock and to wear clothing that protects against sun exposure. Instruct patients to report symptoms of photosensitivity reaction or rash to their physician. Temporary dosage reductions or discontinuations may be required [see WARNINGS AND PRECAUTIONS]. Gastrointestinal Events Instruct patients to report symptoms of persistent gastrointestinal effects including nausea, diarrhea, dyspepsia, vomiting, gastro-esophageal reflux disease, and abdominal pain. Temporary dosage reductions or discontinuations may be required [see WARNINGS AND PRECAUTIONS]. Smokers Encourage patients to stop smoking prior to treatment with ESBRIET and to avoid smoking when using ESBRIET [see CLINICAL PHARMACOLOGY]. Take With Food Instruct patients to take ESBRIET with food to help decrease nausea and dizziness. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenesis Long-term studies were conducted in mice and rats with admixture of pirfenidone to the diet to evaluate its carcinogenic potential. In a 24-month carcinogenicity study in B6C3F1 mice, pirfenidone caused statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma and hepatoblastoma in male mice at doses of 800 mg/kg and above (AUC exposure approximately 0.4 times adult exposure at the MRDD). There were statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma in female mice at doses of 2000 mg/kg and above (AUC exposure approximately 0.7 times adult exposure at the MRDD). In a 24-month carcinogenicity study in Fischer rats, pirfenidone caused statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma in male rats at doses of 750 mg/kg and above (AUC exposure approximately 1.9 times adult exposure at the MRDD). There were statistically significant increases of the combination of hepatocellular adenoma and carcinoma and the combination of uterine adenocarcinoma and adenoma at a dose of 1500 mg/kg/day (AUC exposure approximately 3.0 times adult exposure at the MRDD). The relevance of these tumor findings in rodents to humans is unknown. Mutagenesis Pirfenidone was not mutagenic or clastogenic in the following tests: mutagenicity tests in bacteria, a chromosomal aberration test in Chinese hamster lung cells, and a micronucleus test in mice. Impairment Of Fertility Pirfenidone had no effects on fertility and reproductive performance in rats at dosages up to 1000 mg/kg/day (approximately 3 times the MRDD in adults on a mg/m² basis). Use In Specific Populations Pregnancy Risk Summary The data with ESBRIET use in pregnant women are insufficient to inform on 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 [see Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Animal reproductive studies were conducted in rats and rabbits. In a combined fertility and embryofetal development study, female rats received pirfenidone at oral doses of 0, 50, 150, 450, and 1000 mg/kg/day from 2 weeks prior to mating, during the mating phase, and throughout the periods of early embryonic development from gestation days (GD) 0 to 5 and organogenesis from GD 6 to 17. In an embryofetal development study, pregnant rabbits received pirfenidone at oral doses of 0, 30, 100, and 300 mg/kg/day throughout the period of organogenesis from GD 6 to 18. In these studies, pirfenidone at doses up to 3 and 2 times, respectively, the maximum recommended daily dose (MRDD) in adults (on mg/m² basis at maternal oral doses up to 1000 mg/kg/day in rats and 300 mg/kg/day in rabbits, respectively) revealed no evidence of impaired fertility or harm to the fetus due to pirfenidone. In the presence of maternal toxicity, acyclic/irregular cycles (e.g., prolonged estrous cycle) were seen in rats at doses approximately equal to and higher than the MRDD in adults (on a mg/m² basis at maternal doses of 450 mg/kg/day and higher). In a pre- and post-natal development study, female rats received pirfenidone at oral doses of 0, 100, 300, and 1000 mg/kg/day from GD 7 to lactation day 20. Prolongation of the gestation period, decreased numbers of live newborn, and reduced pup viability and body weights were seen in rats at an oral dosage approximately 3 times the MRDD in adults (on a mg/m² basis at a maternal oral dose of 1000 mg/kg/day). Lactation Risk Summary No information is available on the presence of pirfenidone in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. The lack of clinical data during lactation precludes clear determination of the risk of ESBRIET to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ESBRIET and the potential adverse effects on the breastfed child from ESBRIET or from the underlying maternal condition. Data Animal Data A study with radio-labeled pirfenidone in rats has shown that pirfenidone or its metabolites are excreted in milk. There are no data on the presence of pirfenidone or its metabolites in human milk, the effects of pirfenidone on the breastfed child, or its effects on milk production. Pediatric Use Safety and effectiveness of ESBRIET in pediatric patients have not been established. Geriatric Use 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. Hepatic Impairment 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]. 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]. Renal Impairment ESBRIET should be used with caution in patients with mild (CLcr 50-80 mL/min), moderate (CLcr 30-50 mL/min), or severe (CLcr less than 30 mL/min) renal impairment [see CLINICAL PHARMACOLOGY]. Monitor for adverse reactions and consider dosage modification or discontinuation of ESBRIET as needed [see DOSAGE AND ADMINISTRATION]. 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. Smokers Smoking causes decreased exposure to ESBRIET [see CLINICAL PHARMACOLOGY], 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.