Pirfenidone

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Pirfenidone Prescribing Information

Adverse Reactions (

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)
Adverse Reaction	Pirfenidone 2403 mg/day (N = 623)	Placebo (N = 624)
Nausea	36%	16%
Rash	30%	10%
Abdominal PainIncludes 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%).

) 2/2022

Take with food.

Recommended dosage: 801 mg three times daily (2403 mg/day). (

2 DOSAGE AND ADMINISTRATION

Take with food.
Recommended dosage: 801 mg three times daily (2403 mg/day).
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.
Prior to treatment, conduct liver function tests.

2.1 Testing Prior to Pirfenidone Tablets Administration

Conduct liver function tests prior to initiating treatment with pirfenidone

[see Warnings and Precautions (5.1)].

2.2 Recommended Dosage

The recommended daily maintenance dosage of pirfenidone 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 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 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), consider temporary dosage reductions or interruptions of pirfenidone to allow for resolution of symptoms

[see Warnings and Precautions (5.1, 5.2, 5.3)].

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 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.
Do not rechallenge patient with pirfenidone.

If a patient exhibits >5 × ULN ALT and/or AST:

Permanently discontinue pirfenidone.
Do not rechallenge patient with pirfenidone.

2.4 Dosage Modification due to Drug Interactions

Strong CYP1A2 Inhibitors (e.g., fluvoxamine, enoxacin)

Reduce pirfenidone 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 to 534 mg three times a day (1602 mg/day).

)

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 Dosage Modifications due to Adverse Reactions
Patients who miss 14 or more days of pirfenidone 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), consider temporary dosage reductions or interruptions of pirfenidone to allow for resolution of symptoms
[see Warnings and Precautions (5.1, 5.2, 5.3)].
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 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.
- Do not rechallenge patient with pirfenidone.
If a patient exhibits >5 × ULN ALT and/or AST:
- Permanently discontinue pirfenidone.
- Do not rechallenge patient with pirfenidone.
,
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 ≥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 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, 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
[see Dosage and Administration (2.3)]
.
,
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 (>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)]
.
)
Prior to treatment, conduct liver function tests. (
2.1 Testing Prior to Pirfenidone Tablets Administration
Conduct liver function tests prior to initiating treatment with pirfenidone
[see Warnings and Precautions (5.1)].
)

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 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)]
.
,
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-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 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-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 (CLcr 50 to 80 mL/min), moderate (CLcr 30 to 50 mL/min), and severe (CLcr less than 30 mL/min) renal impairment (n=6/group) and in 6 subjects with normal CLcr (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-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 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/m²) 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 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 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-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 microM) was evaluated in the absence and presence of pirfenidone at concentrations ranging from 1 to 1000 microM in
in vitro
system. Pirfenidone showed weak inhibition (10 to 30%) of Pgp facilitated digoxin B-A efflux at concentrations of 100 microM 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 1000 microM (approximately 10-fold the mean human C_max). Pirfenidone showed a concentration-dependent inhibition on CYP2C9, 2C19 or 1A2, 2D6, and 3A4. At 1000 microM, 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.
)
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 Renal Impairment
Pirfenidone should be used with caution in patients with mild (CLcr 50–80 mL/min), moderate (CLcr 30–50 mL/min), or severe (CLcr 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.
,
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-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 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-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 (CLcr 50 to 80 mL/min), moderate (CLcr 30 to 50 mL/min), and severe (CLcr less than 30 mL/min) renal impairment (n=6/group) and in 6 subjects with normal CLcr (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-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 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/m²) 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 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 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-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 microM) was evaluated in the absence and presence of pirfenidone at concentrations ranging from 1 to 1000 microM in
in vitro
system. Pirfenidone showed weak inhibition (10 to 30%) of Pgp facilitated digoxin B-A efflux at concentrations of 100 microM 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 1000 microM (approximately 10-fold the mean human C_max). Pirfenidone showed a concentration-dependent inhibition on CYP2C9, 2C19 or 1A2, 2D6, and 3A4. At 1000 microM, 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.
)
Smokers: Decreased exposure has been noted in smokers which may alter the efficacy profile of pirfenidone. (
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.
)

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