2.1 Testing Prior to Pirfenidone Tablet 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 tablet 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 Pirfenidone Tablets in Patients with IPF

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.

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 Modifications 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 (1602 mg/day).

5.1 Elevated Liver Enzymes and Drug-Induced Liver Injury

Cases of drug-induced liver injury (DILI) have been observed with pirfenidone tablets. In the postmarketing period, non-serious and serious cases of DILI, including severe liver injury with fatal outcome, have been reported. Patients treated with pirfenidone tablets 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 pirfenidone tablets 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 pirfenidone tablets, 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)].

5.2 Photosensitivity Reaction or Rash

Patients treated with pirfenidone tablets 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)] .

5.3 Severe Cutaneous Adverse Reactions

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 pirfenidone tablets in the postmarketing setting. If signs or symptoms of SCAR occur, interrupt pirfenidone tablets treatment until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, permanently discontinue pirfenidone tablets.

5.4 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 pirfenidone tablets 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 pirfenidone tablets 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)] .

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 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)

7.1 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 tablets and fluvoxamine or other strong CYP1A2 inhibitors (e.g., enoxacin) is not recommended because it significantly increases exposure to pirfenidone tablets [see Clinical Pharmacology (12.3)]. Use of fluvoxamine or other strong CYP1A2 inhibitors should be discontinued prior to administration of pirfenidone tablets and avoided during pirfenidone tablets 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 tablets as needed [see Dosage and Administration (2.4)] .

Moderate CYP1A2 Inhibitors

Concomitant administration of pirfenidone tablets and ciprofloxacin (a moderate inhibitor of CYP1A2) moderately increases exposure to pirfenidone tablets [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 tablets (i.e., CYP2C9, 2C19, 2D6, and 2E1) should be discontinued prior to and avoided during pirfenidone tablets  treatment.

7.2 CYP1A2 Inducers

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

8.1 Pregnancy

Risk Summary

The data with pirfenidone tablets 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 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/m 2basis 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/m 2basis 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/m 2basis at a maternal oral dose of 1000 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 tablets 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 tablets and the potential adverse effects on the breastfed child from pirfenidone tablets 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 tablets in pediatric patients have not been established.

8.5 Geriatric Use

Of the total number of subjects in the clinical studies receiving pirfenidone tablets, 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.

8.6 Hepatic Impairment

Pirfenidone tablets 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 pirfenidone tablets as needed [see Dosage and Administration (2.3)] .

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

8.7 Renal Impairment

Pirfenidone tablets should be used with caution in patients with mild (CL cr50 to 80 mL/min), moderate (CL cr30 to 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 pirfenidone tablets as needed [see Dosage and Administration (2.3)] . The safety, efficacy, and pharmacokinetics of pirfenidone tablets have not been studied in patients with end-stage renal disease requiring dialysis. Use of pirfenidone tablets in patients with end-stage renal diseases requiring dialysis is not recommended.

8.8 Smokers

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

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Cardiac Electrophysiology:

The effect of pirfenidone tablets on QT interval was evaluated in a randomized, placebo, and positive controlled parallel study in 160 healthy adult volunteers. Volunteers received pirfenidone tablets 2403 mg/day (recommended dose) and 4005 mg/day (1.6 times recommended dose) or placebo for 10 days or a single dose of 400 mg moxifloxacin (active control).

Relative to placebo, the maximum mean change from baseline in study-specific QT interval was 3.2 milliseconds (ms) and 2.2 ms for pirfenidone tablets 2403 mg/day and 4005 mg/day, respectively. No volunteer had a QTc interval greater than 480 ms or change from baseline greater than 60 ms. Although there was no evidence that pirfenidone tablets prolonged the QTc interval in this study, a definitive conclusion may not be drawn as the positive control (moxifloxacin) did not perform as expected in this study, and pirfenidone tablets at 4005 mg/day (1.7 times the maximum recommended dose) did not cover the maximum pirfenidone exposure increase with co-administration of fluvoxamine, a strong CYP1A2 inhibitor.

12.3 Pharmacokinetics

Absorption:

After single oral-dose administration of 801 mg pirfenidone (three 267 mg capsules), the maximum observed plasma concentration (C max) was achieved between 30 minutes and 4 hours (median time of 0.5 hours). Food decreased the rate and extent of absorption. Median T maxincreased from 0.5 hours to 3 hours with food. Maximum plasma concentrations (C max) and AUC 0 to infdecreased by approximately 49% and 16% with food, respectively.

Bioequivalence was demonstrated in the fasted state when comparing the 801 mg tablet to three 267 mg capsules. The effect of food on pirfenidone exposure was consistent between the tablet and capsule formulations.

A reduced incidence of adverse reactions was observed in the fed group when compared to the fasted group. In controlled studies with IPF patients, pirfenidone tablets was taken with food [see Dosage and Administration (2) and Clinical Studies (14)] .

The absolute bioavailability of pirfenidone has not been determined in humans.

Distribution:

Pirfenidone binds to human plasma proteins, primarily to serum albumin, in a concentration- independent manner over the range of concentrations observed in clinical trials. The overall mean binding was 58% at concentrations observed in clinical studies (1 to 10 mcg/mL). Mean apparent oral volume of distribution is approximately 59 to 71 liters.

Metabolism:

In vitroprofiling studies in hepatocytes and liver microsomes have shown that pirfenidone is primarily metabolized in the liver by CYP1A2 and multiple other CYPs (CYP2C9, 2C19, 2D6, and 2E1). Oral administration of pirfenidone tablets results in the formation of four metabolites. In humans, only pirfenidone and 5-carboxy-pirfenidone are present in plasma in significant quantities. The mean metabolite-to-parent ratio ranged from approximately 0.6 to 0.7.

No formal radiolabeled studies have assessed the metabolism of pirfenidone in humans. In vitrodata suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations.

Elimination:

The mean terminal half-life is approximately 3 hours in healthy subjects. Pirfenidone is excreted predominantly as metabolite 5-carboxy-pirfenidone, mainly in the urine (approximately 80% of the dose). The majority of pirfenidone was excreted as the 5-carboxy metabolite (approximately 99.6% of that recovered).

Specific Populations:

Hepatic Impairment

The pharmacokinetics of pirfenidone and the 5-carboxy-pirfenidone metabolite were studied in 12 subjects with moderate hepatic impairment (Child Pugh Class B) and in 12 subjects with normal hepatic function. Results showed that the mean exposure, AUC 0 to infand C maxof pirfenidone increased approximately 1.6- and approximately 1.4-fold in subjects with moderate hepatic impairment, respectively. The exposure of 5-carboxy-pirfenidone did not change significantly in subjects with moderate hepatic impairment.

Renal Impairment

The pharmacokinetics of pirfenidone and the 5-carboxy-pirfenidone metabolite were studied in 18 subjects with mild (CL cr50 to 80 mL/min), moderate (CL cr30 to 50 mL/min), and severe (CL crless than 30 mL/min) renal impairment (n=6/group) and in 6 subjects with normal CL cr(greater than or equal to 80 mL/min) renal function. Results showed that systemic exposure (AUC 0 to inf) to pirfenidone increased approximately 1.4, 1.5, and 1.2-fold in subjects with mild, moderate and severe renal impairment, respectively. The corresponding AUC 0 to infof 5-carboxy-pirfenidone increased 1.7, 3.4, and 5.6-fold, although the change in the patients with mild renal impairment was not statistically significant. The renal clearance of 5-carboxy-pirfenidone decreased significantly in patients with moderate to severe renal impairment.

The pharmacokinetics and safety of pirfenidone tablets has not been studied in subjects with end- stage renal disease requiring dialysis.

Geriatric

Results of population pharmacokinetic analysis suggest that no dosage adjustment is needed in geriatric patients.

Gender

Results of population pharmacokinetic analysis of pirfenidone tablets showed no significant differences in pharmacokinetics between males and females.

Obesity

Results of population pharmacokinetic analysis showed that obesity (Body Mass Index  [BMI] greater than or equal to 30 kg/m 2) has no significant effect on the pharmacokinetics of pirfenidone tablets.

Race

Population pharmacokinetic analysis showed that race has no significant effect on the pharmacokinetics of pirfenidone.

Drug Interaction Studies:

Cytochrome P450 1A2 Inhibitors

Pirfenidone is a substrate of cytochrome P450 1A2. In a single-dose drug interaction study in 25 healthy nonsmokers and 25 smokers, pirfenidone tablets 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 approximately 4-fold increase in exposure to pirfenidone in nonsmokers and approximately 7-fold increase in exposure in smokers was observed.

In a single-dose drug interaction study in 27 healthy subjects, coadministration of 801 mg of pirfenidone tablets and 750 mg of ciprofloxacin (a moderate inhibitor of CYP1A2) on Day 6 (ciprofloxacin was dosed at 750 mg twice daily from Day 2 to Day 7) increased the exposure to pirfenidone by 81%.

Cytochrome P450 1A2 Inducers

Following a single oral dose of 801 mg pirfenidone tablets in 25 smokers and 25 healthy nonsmokers, the systemic exposure in smokers was significantly lower compared to nonsmokers. AUC 0 to infand C maxof pirfenidone in smokers were 46% and 68% of those in nonsmokers, respectively.

Inhibitory Effect of Pirfenidone on P-glycoprotein (Pgp)

The potential for pirfenidone to inhibit Pgp mediated transport of digoxin (5.0 µM) was evaluated in the absence and presence of pirfenidone at concentrations ranging from 1 to 1000 µM in in vitrosystem. Pirfenidone showed weak inhibition (10 to 30%) of Pgp facilitated digoxin B to A efflux at concentrations of 100 µM and above. Effect of pirfenidone upon Pgp substrate pharmacokinetics and safety has not been evaluated in humans.

Inhibitory Effect of Pirfenidone on CYP2C9, 2C19 or 1A2, 2D6, 3A4

The potential for pirfenidone to inhibit CYP2C9, 2C19 or 1A2 was evaluated in vitroat concentrations up to 1000 µM (approximately 10-fold the mean human C max). Pirfenidone showed a concentration-dependent inhibition on CYP2C9, 2C19 or 1A2, 2D6, and 3A4. At 1000 µM, pirfenidone inhibits the activity of these enzymes by 30.4%, 27.5%, 34.1%, 21%, and 9.6%, respectively. Effect of pirfenidone upon pharmacokinetics and safety of CYP2C9, 2C19, 1A2, 2D6, and 3A4 substrates has not been evaluated in humans.

13.1 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 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/m 2basis).