Pirfenidone

1 INDICATIONS AND USAGE Pirfenidone capsules are indicated for the treatment of idiopathic pulmonary fibrosis (IPF). Pirfenidone is 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 Capsules Administration Conduct liver function tests prior to initiating treatment with pirfenidone capsules [see Warnings and Precautions (5.1) ]. 2.2 Recommended Dosage The recommended daily maintenance dosage of pirfenidone capsule 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 Capsules 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 capsules 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 capsules to allow for resolution of symptoms. If a SCAR is confirmed, permanently discontinue pirfenidone capsules [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 capsules 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 pirfenidone capsules. Do not rechallenge patient with pirfenidone capsules. If a patient exhibits >5 × ULN ALT and/or AST: Permanently discontinue pirfenidone capsules. Do not rechallenge patient with pirfenidone capsules. 2.4 Dosage Modifications due to Drug Interactions Strong CYP1A2 Inhibitors (e.g., fluvoxamine, enoxacin) Reduce pirfenidone capsules 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 capsules to 534 mg three times a day (1,602 mg/day).

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 AvKARE at 1-855-361-3993 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 1,400 subjects with over 170 subjects exposed to pirfenidone for more than 5 years in clinical trials. Pirfenidone was studied in 3 randomized, double-blind, placebo-controlled trials (Studies 1, 2, and 3) in which a total of 623 patients received 2,403 mg/day of pirfenidone 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 was 62 weeks (range: 2 to 118 weeks) in these 3 trials. At the recommended dosage of 2,403 mg/day, 14.6% of patients on pirfenidone 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 than placebo treatment group are listed in Table 2. Table 2: Adverse Reactions Occurring in ≥ 10% of Pirfenidone-Treated Patients and More Commonly Than Placebo in Studies 1, 2, and 3 Adverse Reaction % of Patients (0 to 118 Weeks) Pirfenidone 2,403 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-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 Post-marketing 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)

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 max increased from 0.5 hours to 3 hours with food. Maximum plasma concentrations (C max ) and AUC 0-inf decreased 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 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 vitro profiling 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 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 vitro data 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-inf and C max of 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 cr 50 to 80 mL/min), moderate (CL cr 30 to 50 mL/min), and severe (CL cr less 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-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-inf of 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 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 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. 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 was co-administered 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, co-administration of 801 mg of pirfenidone 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 in 25 smokers and 25 healthy nonsmokers, the systemic exposure in smokers was significantly lower compared to nonsmokers. AUC 0-inf and C max of 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 1,000 μM in in vitro system. Pirfenidone showed weak inhibition (10% to 30%) of Pgp facilitated digoxin B-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 vitro at concentrations up to 1,000 μM (approximately 10-fold the mean human C max ). Pirfenidone showed a concentration-dependent inhibition on CYP2C9, 2C19 or 1A2, 2D6, and 3A4. At 1,000 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.