PIRFENIDONE: 37,933 Adverse Event Reports & Safety Profile

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

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

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 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 capsules are 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 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 (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 capsules should re-initiate treatment by undergoing the initial 2-week titration regimen up to the full maintenance dosage <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.4 )]</span> .

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 (1602 mg/day).

None. None.

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 Sandoz Inc., at 1-800-525-8747 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 (&gt;1%) adverse reactions leading to discontinuation were rash and nausea. The most common (&gt;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 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 Includes abdominal pain, upper abdominal pain, abdominal distension, and stomach discomfort. 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% 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)

AND PRECAUTIONS Elevated liver enzymes and drug-induced liver injury: ALT, AST, and bilirubin elevations have occurred with pirfenidone including cases of drug-induced liver injury. In the postmarketing setting, non-serious and serious cases of drug-induced liver injury, including severe liver injury with fatal outcomes, have been reported. Monitor ALT, AST, and bilirubin before and during treatment. Temporary dosage reductions or discontinuations may be required. (2.1 , 5.1 ) Photosensitivity and rash: Photosensitivity and rash have been noted with pirfenidone. Avoid exposure to sunlight and sunlamps. Wear sunscreen and protective clothing daily. Temporary dosage reductions or discontinuations may be required. ( 5.2 )

Severe Cutaneous Adverse

Reactions (SCAR): Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS) have been reported in association with the use of pirfenidone in the postmarketing setting. Interrupt pirfenidone in case of signs or symptoms of SCAR. Permanently discontinue pirfenidone if a SCAR is confirmed. ( 5.3 ) Gastrointestinal disorders: Nausea, vomiting, diarrhea, dyspepsia, gastro­-esophageal reflux disease, and abdominal pain have occurred with pirfenidone. Temporary dosage reductions or discontinuations may be required. ( 5.4 )

5.1 Elevated Liver Enzymes and Drug-Induced Liver Injury Cases of drug-induced liver injury (DILI) have been observed with pirfenidone. 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 2403 mg/day in three Phase 3 trials had a higher incidence of elevations in ALT or AST ≥3x ULN than placebo patients (3.7% vs 0.8%, respectively). Elevations ≥10xULN 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 ≥3x 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, 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 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span>.

5.3 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 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 2403 mg/day group discontinued treatment due to a gastrointestinal event, as compared to 1.0% in the placebo group. The most common (&gt;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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span>.

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 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 2403 mg/day group discontinued treatment due to a gastrointestinal event, as compared to 1.0% in the placebo group. The most common (&gt;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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span>.

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>. 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . If ciprofloxacin at the dosage of 750 mg twice daily cannot be avoided, dosage reductions are recommended <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span>. 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .