Pirfenidone

RECENT MAJOR CHANGES Dosage and Administration (2.3) 02/2023 Warnings and Precautions (5.3) 02/2023

1 INDICATIONS AND USAGE Pirfenidone tablets are indicated for the treatment of idiopathic pulmonary fibrosis (IPF). Pirfenidone tablets are a pyridone indicated for the treatment of idiopathic pulmonary fibrosis (IPF). ( 1 )

2 DOSAGE AND ADMINISTRATION • Take with food. • Recommended dosage: 801 mg three times daily (2,403 mg/day). (2) • Upon initiation of treatment, titrate to the full dosage of 2,403 mg/day over a 14-day period as follows: Treatment days Dosage Days 1 through 7 267 mg three times daily (801 mg/day) Days 8 through 14 534 mg three times daily (1,602 mg/day) Days 15 onward 801 mg three times daily (2,403 mg/day) • 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) 2.1 Testing Prior to Pirfenidone Tablets Administration Conduct liver function tests prior to initiating treatment with pirfenidone tablets [see Warnings and Precautions (5.1)] . 2.2 Recommended Dosage The recommended daily maintenance dosage of pirfenidone tablets is 801 mg three times daily for a total of 2,403 mg/day. Doses should be taken with food at the same time each day. Upon initiation of treatment, titrate to the full dosage of 2,403 mg/day over a 14-day period as follows: Table 1. Dosage Titration for Pirfenidone Tablets 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 (1,602 mg/day) Days 15 onward 801 mg three times daily (2,403 mg/day) Dosages above 2,403 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. 2.3 Dosage Modifications due to Adverse Reactions Patients who miss 14 or more days of pirfenidone tablets 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 pirfenidone tablets to allow for resolution of symptoms. If a SCAR is confirmed, permanently discontinue pirfenidone tablets [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.4)]. 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 pirfenidone tablets 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 × ULN ALT and/or AST accompanied by symptoms or hyperbilirubinemia: • Permanently discontinue pirfenidone tablets. • Do not rechallenge patient with pirfenidone tablets. If a patient exhibits >5 × ULN ALT and/or AST: • Permanently discontinue pirfenidone tablets. • Do not rechallenge patient with pirfenidone tablets. 2.4 Dosage Modification due to Drug Interactions Strong CYP1A2 Inhibitors (e.g., fluvoxamine, enoxacin) Reduce pirfenidone tablets 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 pirfenidone tablets to 534 mg three times a day (1,602 mg/day).

3 DOSAGE FORMS AND STRENGTHS Capsules: 267 mg, white opaque hard gelatin capsules containing white to off-white powder and “LA267” printed with brown ink on the cap of the capsule. Film-coated tablets: 267 mg - Yellow colored, oval shaped, biconvex film-coated tablets, debossed with “LP2” on one side and plain on other side. 534 mg - Orange colored, oval shaped, biconvex film-coated tablets, debossed with “LP5” on one side and plain on other side. 801 mg - Brown colored, oval shaped, biconvex film-coated tablets, debossed with “LP8” on one side and plain on other side. Capsules: 267 mg (3) Tablets: 267 mg, 534 mg and 801 mg (3)

4 CONTRAINDICATIONS None. None.

6 ADVERSE REACTIONS 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 )] The most common adverse reactions (≥10%) are nausea, rash, abdominal pain, upper respiratory tract infection, diarrhea, fatigue, headache, decreased appetite, dyspepsia, dizziness, vomiting, gastro-esophageal reflux disease, sinusitis, insomnia, weight decreased, and arthralgia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Micro Labs USA Inc. at 1-855-839-8195 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. Pirfenidone tablets 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 pirfenidone tablets 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 pirfenidone tablets 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 pirfenidone tablets 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 pirfenidone tablets than placebo treatment group are listed in Table 2. Table 2. Adverse Reactions Occurring in ≥10% of Pirfenidone Tablets-Treated Patients and More Commonly Than Placebo in Studies 1, 2, and 3 Adverse Reaction % of Patients (0 to 118 Weeks) Pirfenidone Tablets 2403 mg/day (N = 623) Placebo (N = 624) Nausea 36% 16% Rash 30% 10% Abdominal Pain 1 24% 15% Upper Respiratory Tract Infection 27% 25% Diarrhea 26% 20% Fatigue 26% 19% Headache 22% 19% Decreased Appetite 21% 8% Dyspepsia 19% 7% Dizziness 18% 11% Vomiting 13% 6% 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 pirfenidone tablets-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%). 6.2 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 Hepatobiliary Disorders: Drug-induced liver injury Immune System Disorders: Angioedema Skin and Subcutaneous Tissue Disorders: Severe Cutaneous Adverse Reactions (SCAR)

7 DRUG INTERACTIONS 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) ] Gastrointestinal Disorders [see Warnings and Precautions (5.3) ] Moderate (e.g., ciprofloxacin) and strong inhibitors of CYP1A2 (e.g., fluvoxamine) increase systemic exposure of pirfenidone and may alter the adverse reaction profile of pirfenidone. Discontinue fluvoxamine prior to administration of pirfenidone or reduce to 267 mg three times a day. Consider dosage reduction with use of ciprofloxacin. (7.1) 7.1 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 pirfenidone and fluvoxamine or other strong CYP1A2 inhibitors (e.g., enoxacin) is not recommended because it significantly increases exposure to pirfenidone [see Clinical Pharmacology (12.3) ]. Use of fluvoxamine or other strong CYP1A2 inhibitors should be discontinued prior to administration of pirfenidone and avoided during pirfenidone 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 pirfenidone as needed [ see Dosage and Administration (2.4) ] . Moderate CYP1A2 Inhibitors Concomitant administration of pirfenidone and ciprofloxacin (a moderate inhibitor of CYP1A2) moderately increases exposure to pirfenidone [see Clinical Pharmacology (12.3) ] . If ciprofloxacin at the dosage of 750 mg twice daily cannot be avoided, dosage reductions are recommended [see Dosage and Administration (2.4) ]. 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 pirfenidone (i.e. CYP2C9, 2C19, 2D6, and 2E1) should be discontinued prior to and avoided during pirfenidone treatment. 7.2 CYP1A2 Inducers The concomitant use of pirfenidone and a CYP1A2 inducer may decrease the exposure of pirfenidone and this may lead to loss of efficacy. Therefore, discontinue use of strong CYP1A2 inducers prior to pirfenidone treatment and avoid the concomitant use of pirfenidone and a strong CYP1A2 inducer [see Clinical Pharmacology (12.3) ] .

8 USE IN SPECIFIC POPULATIONS 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) ] Gastrointestinal Disorders [see Warnings and Precautions (5.3) ] Hepatic Impairment: Monitor for adverse reactions and consider dosage modification or discontinuation of pirfenidone as needed. Pirfenidone 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 pirfenidone as needed. Pirfenidone 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 pirfenidone. (8.8) 8.1 Pregnancy Risk Summary The data with pirfenidone 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% to 4% and 15% to 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 1,000 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/m 2 basis at maternal oral doses up to 1,000 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/m 2 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 1,000 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/m 2 basis at a maternal oral dose of 1,000 mg/kg/day). 8.2 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 pirfenidone to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for pirfenidone and the potential adverse effects on the breastfed child from pirfenidone 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. 8.4 Pediatric Use Safety and effectiveness of pirfenidone in pediatri …

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

11 DESCRIPTION Pirfenidone belongs to the chemical class of pyridone. Pirfenidone is available as a white opaque hard gelatin capsules containing 267 mg of pirfenidone USP for oral administration and as film-coated tablets containing 267 mg (yellow), 534 mg (orange) and 801 mg (brown) pirfenidone USP. Pirfenidone has a molecular formula of C 12 H 11 NO and a molecular weight of 185.23. Pirfenidone has the following structural formula, which has been referred to as 5-Methyl-1-Phenyl-1 H -pyridin-2-one or 5-Methyl-1-phenylpyridin-2(1 H )-one. Pirfenidone USP is a white to pale yellow or pink color solid, 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. Pirfenidone capsules, USP contain pirfenidone USP and the following inactive ingredients: croscarmellose sodium, isomalt, and magnesium stearate. In addition, the capsule shell contains gelatin and titanium dioxide. The capsule brown printing ink includes black iron oxide, brown iron oxide, propylene glycol, and shellac. Pirfenidone tablets, USP contain pirfenidone USP and the following inactive ingredients: Colloidal silicon dioxide, croscarmellose sodium, mannitol, microcrystalline cellulose, povidone, and sodium stearyl fumarate. The film-coating material contains polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Additionally 267 mg tablets contain iron oxide yellow. 534 mg tablets contain FD&C yellow #6. 801 mg tablets contain black iron oxide and iron oxide red. Pirfenidone Chemical Structure

10 OVERDOSAGE There is limited clinical experience with overdosage. Multiple dosages of pirfenidone tablets 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Pirfenidone capsules, USP are available in 267 mg and supplied as follows: 267 mg - white opaque hard gelatin capsules containing white to off-white powder and “LA267” printed with brown ink on the cap of the capsule. NDC 42385-923-29, bottle for a 30-day supply containing 270 capsules and closed with a child-resistant closure NDC 42385-923-63, 14-day titration blister pack, carton containing a total of 63 capsules in two blister cards – a Week 1 blister card containing 21 capsules and a Week 2 blister card containing 42 capsules NDC 42385-923-54, 4-week maintenance blister pack, carton containing a total of 252 capsules in four blister cards each with 63 capsules Pirfenidone tablets, USP are available in 267 mg, 534 mg and 801 mg strengths and supplied as follows: 267 mg - Yellow colored, oval shaped, biconvex film-coated tablets, debossed with “LP2” on one side and plain on other side. NDC 42385-924-99, carton containing 3 bottles, each containing ninety 267 mg tablets (270 tablets total) with a child-resistant closure NDC 42385-924-29, bottle containing two hundred and seventy 267 mg tablets, with a child-resistant closure 534 mg - Orange colored, oval shaped, biconvex film-coated tablets, debossed with “LP5” on one side and plain on other side. NDC 42385-925-90, bottle containing ninety 534 mg tablets, with a child-resistant closure 801 mg - Brown colored, oval shaped, biconvex film-coated tablets, debossed with “LP8” on one side and plain on other side. NDC 42385-926-90, bottle containing ninety 801 mg tablets, with a child-resistant closure Store at 20° to 25°C (68° to 77°F), excursions permitted between 15° to 30°C (59° to 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 pirfenidone capsules and tablets that are out of date or no longer needed.