Pirfenidone

Product Type: HUMAN PRESCRIPTION DRUG

Route: ORAL

Dosage Form:

NDC: 62332-479

Application: ANDA212708

Effective: 20231206

1 INDICATIONS AND USAGE Pirfenidone tablets 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 (2403 mg/day). (2) • Upon initiation of treatment, titrate to the full dosage of 2403 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 (1602 mg/day) Days 15 onward 801 mg three times daily (2403 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 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 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. 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 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 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).

4 CONTRAINDICATIONS None. None

Not available.

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 Alembic Pharmaceuticals Limited at 1-866-210-9797 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 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 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 2403 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 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-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)