Pirfenidone

None. None

• 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.
• ( 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.
• ( 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.
• (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 2,403 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 pirfenidone 2,403 mg/day group and in 0.2% of patients in the placebo group.
• Increases in ALT and AST ≥3xULN 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 2,403 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 in the postmarketing setting.
• If signs or symptoms of SCAR occur, interrupt pirfenidone treatment until the etiology of the reaction has been determined.
• Consultation with a dermatologist is recommended.
• 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 2,403 mg/day group, as compared to 5.8% of patients in the placebo group; 2.2% of patients in the pirfenidone 2,403 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)] .

• 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).
• IN SPECIFIC POPULATIONS 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 Labor & Delivery 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 pediatric patients have not been established.
• 8.5 Geriatric Use Of the total number of subjects in the clinical studies receiving pirfenidone, 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 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 as needed [ see Dosage and Administration (2.3)] .
• The safety, efficacy, and pharmacokinetics of pirfenidone have not been studied in patients with severe hepatic impairment.
• Pirfenidone is not recommended for use in patients with severe (Child Pugh Class C) hepatic impairment [see Clinical Pharmacology (12.3)] .
• 8.7 Renal Impairment Pirfenidone should be used with caution in patients with mild (CL cr 50 to 80 mL/min), moderate (CL cr 30 to 50 mL/min), or severe (CL cr less than 30 mL/min) renal impairment [see Clinical Pharmacology (12.3)].
• Monitor for adverse reactions and consider dosage modification or discontinuation of pirfenidone as needed [ see Dosage and Administration (2.3)] .
• The safety, efficacy, and pharmacokinetics of pirfenidone have not been studied in patients with end-stage renal disease requiring dialysis.
• Use of pirfenidone in patients with end-stage renal diseases requiring dialysis is not recommended.
• 8.8 Smokers Smoking causes decreased exposure to pirfenidone [see Clinical Pharmacology (12.3)], which may alter the efficacy profile of pirfenidone.
• Instruct patients to stop smoking prior to treatment with pirfenidone and to
• avoid smoking
• when using pirfenidone.

• 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)] .

• There is limited clinical experience with overdosage.
• Multiple dosages of pirfenidone up to a maximum tolerated dose of 4,005 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.