Indications and
Usage for Esbriet
Esbriet is
indicated for the treatment of idiopathic pulmonary fibrosis (IPF).
Esbriet Dosage
and Administration
Testing Prior to
Esbriet Administration
Conduct liver
function tests prior to initiating treatment with Esbriet [see Warnings and
Precautions (5.1)].
Recommended
Dosage
The recommended
daily maintenance dosage of Esbriet 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 Esbriet 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.
Dosage
Modifications due to Adverse Reactions
Patients who
miss 14 or more days of Esbriet 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 Esbriet 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 Esbriet 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 Esbriet.Do
not rechallenge patient with Esbriet.
If a patient
exhibits >5 × ULN ALT and/or AST:
Permanently
discontinue Esbriet.Do
not rechallenge patient with Esbriet.
Dosage
Modification due to Drug Interactions
Strong CYP1A2
Inhibitors (e.g., fluvoxamine, enoxacin)
Reduce Esbriet
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 Esbriet to 534 mg three
times a day (1602 mg/day).
Dosage Forms and
Strengths
Capsules: 267
mg, white to off-white, hard gelatin capsules printed with "PFD 267
mg" on the cap of the capsule in brown ink.
Film-coated
tablets: oval, biconvex, debossed with "PFD", containing 267 mg
(yellow) and 801 mg (brown) pirfenidone
Contraindications
None.
Warnings and
Precautions
Elevated Liver
Enzymes
Increases in ALT
and AST >3 × ULN have been reported in patients treated with Esbriet. In
some cases these have been associated with concomitant elevations in bilirubin.
Patients treated with Esbriet 2403 mg/day in the 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 Esbriet 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. No cases of liver transplant or death due to
liver failure that were related to Esbriet have been reported. However, the
combination of transaminase elevations and elevated bilirubin without evidence
of obstruction is generally recognized as an important predictor of severe
liver injury, that could lead to death or the need for liver transplants in
some patients. Conduct liver function tests (ALT, AST, and bilirubin) prior to
the initiation of therapy with Esbriet in all patients, then monthly for the
first 6 months and every 3 months thereafter. Dosage modifications or
interruption may be necessary for liver enzyme elevations [see Dosage and
Administration (2.1, 2.3)].
Photosensitivity
Reaction or Rash
Patients treated
with Esbriet 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)].
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 Esbriet 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 Esbriet 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)].
Adverse
Reactions
The following
adverse reactions are discussed in greater detail in other sections of the
labeling:
Liver
Enzyme Elevations [see Warnings
and Precautions (5.1)]Photosensitivity
Reaction or Rash [see Warnings
and Precautions (5.2)]Gastrointestinal
Disorders [see Warnings
and Precautions (5.3)]
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.
Esbriet 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 Esbriet 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 Esbriet 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 Esbriet 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 Esbriet
than placebo treatment group are listed in Table 2.
Table 2. Adverse Reactions Occurring in ≥10% of
Esbriet-Treated Patients and More Commonly Than Placebo in Studies 1, 2, and
3
|
|
|
Adverse Reaction
|
% of Patients (0 to 118 Weeks)
|
|
|
Esbriet 2403 mg/day
(N = 623)
|
Placebo
(N = 624)
|
|
|
*
Includes
abdominal pain, upper abdominal pain, abdominal distension, and stomach
discomfort.
|
|
|
Nausea
|
36%
|
16%
|
|
|
Rash
|
30%
|
10%
|
|
|
Abdominal Pain*
|
24%
|
15%
|
|
|
Upper Respiratory Tract Infection
|
27%
|
25%
|
|
|
Diarrhea
|
26%
|
20%
|
|
|
Fatigue
|
26%
|
19%
|
|
|
Headache
|
22%
|
19%
|
|
|
Dyspepsia
|
19%
|
7%
|
|
|
Dizziness
|
18%
|
11%
|
|
|
Vomiting
|
13%
|
6%
|
|
|
Anorexia
|
13%
|
5%
|
|
|
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 Esbriet-treated patients and more
commonly than placebo are photosensitivity reaction (9% vs. 1%), decreased
appetite (8% vs. 3%), pruritus (8% vs. 5%), asthenia (6% vs. 4%), dysgeusia (6%
vs. 2%), and non-cardiac chest pain (5% vs. 4%).
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
Immune System
Disorders
Angioedema
Hepatobiliary
Disorders
Bilirubin increased in combination with increases of ALT and AST
Drug
Interactions
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 Esbriet and fluvoxamine or other strong CYP1A2 inhibitors
(e.g., enoxacin) is not recommended because it significantly increases exposure
to Esbriet [see Clinical Pharmacology (12.3)]. Use of
fluvoxamine or other strong CYP1A2 inhibitors should be discontinued prior to
administration of Esbriet and avoided during Esbriet 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 Esbriet as needed [see Dosage and
Administration (2.4)].
Moderate CYP1A2
Inhibitors
Concomitant
administration of Esbriet and ciprofloxacin (a moderate inhibitor of CYP1A2)
moderately increases exposure to Esbriet [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 Esbriet
(i.e., CYP2C9, 2C19, 2D6, and 2E1) should be discontinued prior to and avoided
during Esbriet treatment.
CYP1A2 Inducers
The concomitant
use of Esbriet and a CYP1A2 inducer may decrease the exposure of Esbriet and
this may lead to loss of efficacy. Therefore, discontinue use of strong CYP1A2
inducers prior to Esbriet treatment and avoid the concomitant use of Esbriet
and a strong CYP1A2 inducer [see Clinical Pharmacology (12.3)].
USE IN SPECIFIC
POPULATIONS
Pregnancy
Risk Summary
The data with
Esbriet 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 2–4% and 15–20%,
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 1000 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/m2 basis at maternal oral doses up to 1000 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/m2 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 1000 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/m2 basis at a
maternal oral dose of 1000 mg/kg/day).
Lactation
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 Esbriet to an infant during lactation; therefore, the developmental and
health benefits of breastfeeding should be considered along with the mother's
clinical need for Esbriet and the potential adverse effects on the breastfed
child from Esbriet 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.
Pediatric Use
Safety and
effectiveness of Esbriet in pediatric patients have not been established.
Geriatric Use
Of the total
number of subjects in the clinical studies receiving Esbriet, 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.
Hepatic
Impairment
Esbriet 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 Esbriet as needed [see Dosage and
Administration (2.3)].
The safety,
efficacy, and pharmacokinetics of Esbriet have not been studied in patients
with severe hepatic impairment. Esbriet is not recommended for use in patients
with severe (Child Pugh Class C) hepatic impairment [see Clinical
Pharmacology (12.3)].
Renal Impairment
Esbriet 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
Esbriet as needed [see Dosage and Administration (2.3)]. The safety,
efficacy, and pharmacokinetics of Esbriet have not been studied in patients
with end-stage renal disease requiring dialysis. Use of Esbriet in patients
with end-stage renal diseases requiring dialysis is not recommended.
Smokers
Smoking causes
decreased exposure to Esbriet [see Clinical Pharmacology (12.3)], which may
alter the efficacy profile of Esbriet. Instruct patients to stop smoking prior
to treatment with Esbriet and to avoid smoking when using Esbriet.
Overdosage
There is limited
clinical experience with overdosage. Multiple dosages of Esbriet up to a
maximum tolerated dose of 4005 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.
Esbriet
Description
Esbriet belongs
to the chemical class of pyridone. Esbriet is available as a white to off-white
hard gelatin capsule containing 267 mg of pirfenidone for oral administration,
or, as film-coated tablets containing 267 mg (yellow) and 801 mg (brown)
pirfenidone.
Pirfenidone has
a molecular formula of C12H11NO and a
molecular weight of 185.23. Pirfenidone has the following structural formula,
which has been referred to as 5-methyl-1-phenyl-2-1(H)-pyridone or
5-methyl-1-phenyl-2-(1H)-pyridone.
Pirfenidone is a
white to pale yellow, 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.
Esbriet capsule
contains pirfenidone and the following inactive ingredients: microcrystalline
cellulose, croscarmellose sodium, povidone, and magnesium stearate.
In addition, the
capsule shell contains gelatin and titanium dioxide. The capsule brown printing
ink includes shellac, iron oxide black, iron oxide red, iron oxide yellow,
propylene glycol, ammonium hydroxide.
Esbriet tablets
contain pirfenidone and the following inactive ingredients: Microcrystalline
cellulose, colloidal anhydrous silica, povidone, croscarmellose sodium,
magnesium stearate, polyvinyl alcohol, titanium dioxide, macrogol (polyethylene
glycol), talc, and iron oxide.
Esbriet -
Clinical Pharmacology
Mechanism of
Action
The mechanism of
action of pirfenidone in the treatment of IPF has not been established.
Pharmacodynamics
Cardiac
Electrophysiology:
The effect of
Esbriet on QT interval was evaluated in a randomized, placebo, and positive
controlled parallel study in 160 healthy adult volunteers. Volunteers received
Esbriet 2403 mg/day (recommended dose) and 4005 mg/day (1.6 times recommended
dose) or placebo for 10 days or a single dose of 400 mg moxifloxacin (active
control).
Relative to
placebo, the maximum mean change from baseline in study-specific QT interval
was 3.2 milliseconds (ms) and 2.2 ms for Esbriet 2403 mg/day and 4005 mg/day,
respectively. No volunteer had a QTc interval greater than 480 ms or change
from baseline greater than 60 ms. Although there was no evidence that Esbriet
prolonged the QTc interval in this study, a definitive conclusion may not be
drawn as the positive control (moxifloxacin) did not perform as expected in
this study, and Esbriet at 4005 mg/day (1.7 times the maximum recommended dose)
did not cover the maximum pirfenidone exposure increase with co-administration
of fluvoxamine, a strong CYP1A2 inhibitor.
Pharmacokinetics
Absorption:
After single
oral-dose administration of 801 mg Esbriet (three 267 mg capsules), the maximum
observed plasma concentration (Cmax) was achieved between 30 minutes and 4
hours (median time of 0.5 hours). Food decreased the rate and extent of
absorption. Median Tmax increased from 0.5 hours to 3 hours with food.
Maximum plasma concentrations (Cmax) and AUC0-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, Esbriet 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:
Esbriet 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 μg/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 Esbriet is
primarily metabolized in the liver by CYP1A2 and multiple other CYPs (CYP2C9,
2C19, 2D6, and 2E1). Oral administration of Esbriet 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 Esbriet was excreted as the
5-carboxy metabolite (approximately 99.6% of that recovered).
Specific
Populations:
Hepatic
Impairment
The
pharmacokinetics of Esbriet 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, AUC0-inf and Cmax 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 (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 (AUC0-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 AUC0-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 Esbriet 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 Esbriet 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 Esbriet.
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, Esbriet 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
Esbriet 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 Esbriet in 25 smokers and 25 healthy nonsmokers, the
systemic exposure in smokers was significantly lower compared to nonsmokers.
AUC0-inf and Cmax 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 1000 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 1000 µM (approximately 10-fold the mean human Cmax). Pirfenidone
showed a concentration-dependent inhibition on CYP2C9, 2C19 or 1A2, 2D6, and
3A4. At 1000 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.
Nonclinical
Toxicology
Carcinogenesis,
Mutagenesis, Impairment of Fertility
Carcinogenesis
Long-term
studies were conducted in mice and rats with admixture of pirfenidone to the diet
to evaluate its carcinogenic potential.
In a 24-month
carcinogenicity study in B6C3F1 mice, pirfenidone caused statistically
significant dose-related increases of the combination of hepatocellular adenoma
and carcinoma and hepatoblastoma in male mice at doses of 800 mg/kg and above
(AUC exposure approximately 0.4 times adult exposure at the MRDD). There were
statistically significant dose-related increases of the combination of
hepatocellular adenoma and carcinoma in female mice at doses of 2000 mg/kg and
above (AUC exposure approximately 0.7 times adult exposure at the MRDD).
In a 24-month
carcinogenicity study in Fischer rats, pirfenidone caused statistically
significant dose-related increases of the combination of hepatocellular adenoma
and carcinoma in male rats at doses of 750 mg/kg and above (AUC exposure
approximately 1.9 times adult exposure at the MRDD). There were statistically
significant increases of the combination of hepatocellular adenoma and
carcinoma and the combination of uterine adenocarcinoma and adenoma at a dose
of 1500 mg/kg/day (AUC exposure approximately 3.0 times adult exposure at the
MRDD).
The relevance of
these tumor findings in rodents to humans is unknown.
Mutagenesis
Pirfenidone was
not mutagenic or clastogenic in the following tests: mutagenicity tests in
bacteria, a chromosomal aberration test in Chinese hamster lung cells, and a
micronucleus test in mice.
Impairment of
Fertility
Pirfenidone had
no effects on fertility and reproductive performance in rats at dosages up to 1000
mg/kg/day (approximately 3 times the MRDD in adults on a mg/m2 basis).
Clinical Studies
The efficacy of
Esbriet was evaluated in patients with IPF in three phase 3, randomized,
double-blind, placebo-controlled, multicenter trials (Studies 1, 2, and 3).
Study 1 was a
52-week trial comparing Esbriet 2403 mg/day (n=278) versus placebo (n=277) in
patients with IPF. Study 2 and Study 3 were nearly identical to each other in
design, with few exceptions, including an intermediate dose treatment arm in
Study 2. Study 2 compared treatment with either Esbriet 2403 mg/day (n=174) or
Esbriet 1197 mg/day (n=87) to placebo (n=174), while Study 3 compared Esbriet
2403 mg/day (n=171) to placebo (n=173). Study drug was administered three times
daily with food for a minimum of 72 weeks. Patients continued on treatment
until the last patient completed 72 weeks of treatment, which included
observations to approximately 120 weeks of study treatment. The primary
endpoint was the change in percent predicted forced vital capacity (%FVC) from
baseline to study end, measured at 52 weeks in Study 1, and at 72 weeks in
Studies 2 and 3.
Studies 1, 2 and
3 enrolled adult patients who had a clinical and radiographic diagnosis of IPF
(with or without accompanying surgical lung biopsy), without evidence or
suspicion of an alternative diagnosis for interstitial lung disease. Eligible
patients were to have %FVC greater than or equal to 50% at baseline and a
percent predicted diffusing capacity of the lungs for carbon monoxide (%DLCO) greater than
or equal to 30% (Study 1) or 35% (Studies 2 and 3) at baseline. In all three
trials, over 80% of patients completed study treatment.
A total of 1247
patients with IPF were randomized to receive Esbriet 2403 mg/day (n=623) or
placebo (n=624) in these three trials. Baseline characteristics were generally
balanced across treatment groups. The study population ranged from 40 to 80
years of age (mean age 67 years). Most patients were male (74%), white (95%),
and current or former smokers (65%). Approximately 93% of patients met criteria
for definite IPF on high resolution computed tomography (HRCT). Baseline mean
%FVC and %DLCOwere 72% and 46%, respectively. Approximately 15%
subjects discontinued from each treatment group.
Change from
Baseline in Percent Predicted Forced Vital Capacity
In Study 1, the
primary efficacy analysis for the change in %FVC from baseline to Week 52
demonstrated a statistically significant treatment effect of Esbriet 2403
mg/day (n=278) compared with placebo (n=277) using a rank ANCOVA with the
lowest rank imputation for missing data due to death. In Study 2, there was a
statistically significant difference at Week 72 for the change in %FVC from
baseline. In Study 3, there was no statistically significant difference at Week
72 for the change in %FVC from baseline.
Figure 1 presents
the cumulative distribution for all cut-offs for the change from baseline in
%FVC at Week 52 for Study 1. For all categorical declines in lung function, the
proportion of patients declining was lower on Esbriet than on placebo. Study 2
showed similar results.
Figure 1.
Cumulative Distribution of Patients by Change in Percent Predicted FVC from
Baseline to Week 52 (Study 1). The Dashed Lines Indicate ≥10% Decline or ≥0%
Decline.
Mean Change from
Baseline in FVC (mL)
In Study 1, a
reduction in the mean decline in FVC (in mL) was observed in patients receiving
Esbriet 2403 mg/day (-235 mL) compared to placebo (-428 mL) (mean treatment
difference 193 mL) at Week 52 (see Figure 2). In Study 2, a
reduction in the decline in FVC volume was also observed in patients receiving
Esbriet 2403 mg/day compared with placebo (mean treatment difference 157 mL) at
Week 72. There was no statistically significant difference in decline in FVC
volume seen in Study 3.
Figure 2. Mean
Change from Baseline in Forced Vital Capacity (Study 1)
Survival
Survival was
evaluated for Esbriet compared to placebo in Studies 1, 2, and 3 as an
exploratory analysis to support the primary endpoint (FVC). All-cause mortality
was assessed over the study duration and available follow-up period,
irrespective of cause of death and whether patients continued treatment.
All-cause mortality did not show a statistically significant difference
(see Figure 3).
Figure 3.
Kaplan-Meier Estimates of All-Cause Mortality at Vital Status – End of Study:
Studies 1, 2, and 3
How
Supplied/Storage and Handling
Esbriet white to
off-white hard gelatin capsules contain 267 mg of pirfenidone. The cap of the
capsule is printed with "PFD 267 mg" in brown ink. The capsule is
supplied either in a bottle, a 14-day titration blister pack or a 4-week
maintenance blister pack.
Esbriet
film-coated tablets are oval, biconvex, debossed with "PFD",
containing 267 mg (yellow) and 801 mg (brown) pirfenidone. The film-coated
tablets are supplied in bottles.
Esbriet
capsules:
NDC
50242-121-01, bottle for a 30-day supply containing 270 capsules and
closed with a child-resistant closureNDC
50242-121-02, 14-day titration blister pack, carton containing a total of
63 capsules in two blister cards – a Week 1 blister card containing 21
capsules (1 capsule per blister well) and a Week 2 blister card containing
42 capsules (2 capsules per blister well)NDC
50242-121-03, 4-week maintenance blister pack, carton containing a total
of 252 capsules in four blister cards each with 63 capsules (3 capsules
per blister well)
Esbriet
film-coated tablets:
NDC
50242-122-05, carton containing 3 bottles, each containing ninety 267 mg
tablets (270 tablets total) with a child-resistant closureNDC
50242-122-06, carton containing 1 bottle containing 270 tablets, 267 mg
each, with a child-resistant closureNDC
50242-123-01, carton containing 1 bottle containing ninety 801 mg tablets,
with a child-resistant closure
Store at 25°C
(77°F); excursions permitted to 15–30°C (59–86°F) (see USP Controlled Room
Temperature).
Keep the bottle
tightly closed. Do not use if the seal over the bottle opening is broken or
missing. Safely throw away any Esbriet that is out of date or no longer needed.
Patient
Counseling Information
Advise the
patient to read the FDA-approved patient labeling (Patient Information).
Liver Enzyme
Elevations
Advise patients
that they may be required to undergo liver function testing periodically.
Instruct patients to immediately report any symptoms of a liver problem (e.g.,
skin or the white of eyes turn yellow, urine turns dark or brown [tea colored],
pain on the right side of stomach, bleed or bruise more easily than normal,
lethargy) [see Warnings and Precautions (5.1)].
Photosensitivity
Reaction or Rash
Advise patients
to avoid or minimize exposure to sunlight (including sunlamps) during use of
Esbriet because of concern for photosensitivity reactions or rash. Instruct
patients to use a sunblock and to wear clothing that protects against sun
exposure. Instruct patients to report symptoms of photosensitivity reaction or
rash to their physician. Temporary dosage reductions or discontinuations may be
required [see Warnings and Precautions (5.2)].
Gastrointestinal
Events
Instruct
patients to report symptoms of persistent gastrointestinal effects including
nausea, diarrhea, dyspepsia, vomiting, gastro-esophageal reflux disease, and
abdominal pain. Temporary dosage reductions or discontinuations may be
required [see Warnings and Precautions (5.3)].
Smokers
Encourage
patients to stop smoking prior to treatment with Esbriet and to avoid smoking
when using Esbriet [see Clinical Pharmacology (12.3)].
Take with Food
Instruct
patients to take Esbriet with food to help decrease nausea and dizziness.
Distributed by:
Genentech USA, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990
Esbriet® is a
registered U.S. trademark of Genentech, Inc.
© 2016 Genentech, Inc.
|
Patient
Information
Esbriet
(es-BREE-et)
(pirfenidone)
capsules
and film-coated tablets
|
|
This Patient Information has been approved by the U.S.
Food and Drug Administration
|
Revised: October
2017
|
|
What is Esbriet?
Esbriet is a prescription medicine used to
treat people with a lung disease called idiopathic pulmonary fibrosis
(IPF).It is not known if Esbriet is safe and effective
in children.
|
|
Before you take Esbriet,
tell your doctor about all of your medical conditions, including if you:
have liver problemshave kidney problemsare a smokerare pregnant or plan to become pregnant. It is
not known if Esbriet will harm your unborn baby.are breastfeeding or plan to breastfeed. It is
not known if Esbriet passes into your breast milk. You and your doctor
should decide if you will take Esbriet.
Tell your doctor about all the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements.
|
|
How should I take Esbriet?
Take Esbriet exactly as your doctor tells you
to take it.Your doctor may change your dose of Esbriet as
needed.Take Esbriet with food at the same time each day.
This may help to decrease your nausea and dizziness.
o Esbriet 267 mg is supplied
as either a white to off-white capsule or a yellow tablet. If you have been
prescribed Esbriet 267 mg, take it as follows:
o Take 1 Esbriet 267 mg capsule or tablet 3 times each
day for days 1 through 7.
o Take 2 Esbriet 267 mg capsule or tablet 3 times each
day for days 8 through 14.
o Take 3 Esbriet 267 mg capsule or tablet 3 times each
day on day 15 and each day after.
|
|
|
Esbriet 267 mg Dosing
Schedule
|
|
|
|
Week
|
Morning (Breakfast)
|
Afternoon (Lunch)
|
Evening (Dinner)
|
Total Pills Each Day
|
|
|
|
Days 1-7
|
1
|
1
|
1
|
3
|
|
|
|
Days 8-14
|
2
|
2
|
2
|
6
|
|
|
|
Days 15 onward
|
3
|
3
|
3
|
9
|
|
|
|
· If you have been prescribed the brown 801 mg Esbriet film-coated
tablets, take it as follows:
Take 1 brown 801 mg Esbriet tablet 3 times
each day.
|
|
|
Esbriet 801 mg Dosing
Schedule
|
|
|
|
Week
|
Morning (Breakfast)
|
Afternoon (Lunch)
|
Evening (Dinner)
|
Total Pills Each Day
|
|
|
|
Days 15 onward
|
1
|
1
|
1
|
3
|
|
|
· If you miss 14
days or more of Esbriet call your doctor right away for further instructions
about how to take your medicine.
· Do not take 2 doses at the same
time to make up for your missed dose.
· Do not take more than 3 doses
each day.
· If you take too
much Esbriet, call your doctor or go to the nearest hospital emergency room
right away.
· Your doctor
should do certain blood tests before you start taking Esbriet.
|
|
What should I avoid while
taking Esbriet?
· Avoid sunlight.
Esbriet can make your skin sensitive to the sun and the light from sunlamps
and tanning beds. You could get a severe sunburn. Use sunscreen (SPF 50) and
wear a hat and clothes that cover your skin if you have to be in sunlight.
Talk to your doctor if you get sunburn or a rash.
· Avoid taking
Esbriet with other medicines that can make your skin sensitive to the sun,
the light from sunlamps and tanning beds.
· Avoid smoking.
Smoking may affect how well Esbriet works.
|
|
What are the possible side
effects of Esbriet?
Esbriet may cause serious side effects, including:
liver problems. Call your doctor right away if you have
unexplained symptoms such as yellowing of your skin or the white part of
your eyes (jaundice), dark or brown (tea colored) urine, pain on the
upper right side of your stomach area (abdomen), bleeding or bruising
more easily than normal, feeling tired.
Your doctor will do blood tests to check how your liver
is working during your treatment with Esbriet.
sensitivity to sunlight
(photosensitivity) and rash. See "What should
I avoid while taking Esbriet?"stomach problems. Esbriet may cause stomach problems such
as nausea, vomiting, diarrhea, indigestion, heartburn, and stomach pain.
Tell your doctor right away if your stomach problems get worse or do not
go away. Your doctor may need to change your dose of Esbriet.
The most common side effects of Esbriet include feeling tired, insomnia, upper respiratory tract
infections, sinusitis, headache, dizziness, decreased weight and decreased or
loss of appetite.
These are not all the possible side effects of Esbriet. Call your doctor
for medical advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.
|
|
How should I store Esbriet?
Store Esbriet capsules and tablets at room
temperature, 77°F (25°C).Keep in a tightly closed container.
Safely throw away any Esbriet that is out of date or no longer
needed. Keep
Esbriet and all medicines out of reach of children.
|
|
General information about
the safe and effective use of Esbriet.
Medicines are sometimes prescribed for purposes other than those listed
in a Patient Information leaflet. Do not use Esbriet for a condition for
which it was not prescribed. Do not give Esbriet to other people, even if
they have the same symptoms that you have. It may harm them. You can ask your
pharmacist or doctor for information about Esbriet that is written for health
professionals.
|
|
What are the ingredients in
Esbriet capsules?
Active ingredient: pirfenidone
Inactive ingredients: microcrystalline cellulose, croscarmellose sodium, povidone, and
magnesium stearate
Capsule Shell: gelatin and titanium dioxide
Capsule Brown Printing Ink: shellac, iron oxide black, iron oxide red, iron
oxide yellow, propylene glycol, ammonium hydroxide
What are the ingredients in Esbriet film-coated
tablets?
Active ingredient: pirfenidone
Inactive ingredients: microcrystalline cellulose, colloidal anhydrous silica, povidone,
croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium
dioxide, macrogol (polyethylene glycol), talc, and iron oxide
For more information, go to www.Esbriet.com or call 1-888-835-2555.
© 2016
Genentech, Inc.
|
Representative
sample of labeling (see the HOW SUPPLIED section
for complete listing):
PRINCIPAL
DISPLAY PANEL - 267 mg Bottle Carton
NDC 50242-121-01
Esbriet®
(pirfenidone)
capsules
267 mg
Keep out of
reach of children.
Rx only
270 Capsules
Genentech
10164280
PRINCIPAL
DISPLAY PANEL - 267 mg Capsule Blister Pack Carton
Esbriet®
(pirfenidone)
capsules
NDC 50242-121-87
SAMPLE - NOT FOR
SALE
267 mg
Keep out of
reach of children.
Rx only
189 Capsules
Genentech
10171840
4-week treatment
pack of 189 capsules. Contains enough capsules for 4 weeks.
PRINCIPAL
DISPLAY PANEL - 267 mg Tablet Bottle Carton
NDC 50242-122-06
Esbriet®
(pirfenidone)
tablets
267 mg
Keep out of
reach of children.
Rx only
270 tablets
Genentech
10190520
PRINCIPAL DISPLAY
PANEL - 801 mg Tablet Bottle Carton
NDC 50242-123-01
Esbriet®
(pirfenidone)
tablets
801 mg
Keep out of
reach of children.
Rx only
90 tablets
Genentech
10181492
|
Esbriet pirfenidone
capsule
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:50242-121
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
PIRFENIDONE (PIRFENIDONE)
|
PIRFENIDONE
|
267 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
CROSCARMELLOSE SODIUM
|
|
|
MICROCRYSTALLINE CELLULOSE
|
|
|
POVIDONE, UNSPECIFIED
|
|
|
MAGNESIUM STEARATE
|
|
|
TITANIUM DIOXIDE
|
|
|
GELATIN, UNSPECIFIED
|
|
|
SHELLAC
|
|
|
|
Product Characteristics
|
|
Color
|
WHITE (Off-White)
|
Score
|
no score
|
|
Shape
|
CAPSULE
|
Size
|
19mm
|
|
Flavor
|
|
Imprint Code
|
PFD;267;mg
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:50242-121-01
|
1 BOTTLE, PLASTIC in 1 CARTON
|
|
|
1
|
|
270 CAPSULE in 1 BOTTLE, PLASTIC
|
|
|
2
|
NDC:50242-121-87
|
1 BLISTER PACK in 1 CARTON
|
|
|
2
|
|
63 CAPSULE in 1 BLISTER PACK
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA022535
|
10/15/2014
|
|
|
|
Esbriet pirfenidone
tablet, coated
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:50242-122
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
PIRFENIDONE (PIRFENIDONE)
|
PIRFENIDONE
|
267 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
MICROCRYSTALLINE CELLULOSE
|
|
|
SILICON DIOXIDE
|
|
|
POVIDONE K30
|
|
|
CROSCARMELLOSE SODIUM
|
|
|
MAGNESIUM STEARATE
|
|
|
POLYVINYL ALCOHOL,
UNSPECIFIED
|
|
|
TITANIUM DIOXIDE
|
|
|
POLYETHYLENE GLYCOL 3350
|
|
|
TALC
|
|
|
FERRIC OXIDE YELLOW
|
|
|
|
Product Characteristics
|
|
Color
|
YELLOW (Pale Yellow)
|
Score
|
no score
|
|
Shape
|
OVAL
|
Size
|
13mm
|
|
Flavor
|
|
Imprint Code
|
PFD
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:50242-122-05
|
3 BOTTLE, PLASTIC in 1 CARTON
|
|
|
1
|
|
90 TABLET, COATED in 1 BOTTLE, PLASTIC
|
|
|
2
|
NDC:50242-122-86
|
1 BOTTLE, PLASTIC in 1 CARTON
|
|
|
2
|
|
189 TABLET, COATED in 1 BOTTLE, PLASTIC
|
|
|
3
|
NDC:50242-122-06
|
1 BOTTLE, PLASTIC in 1 CARTON
|
|
|
3
|
|
270 TABLET, COATED in 1 BOTTLE, PLASTIC
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA208780
|
01/11/2017
|
|
|
|
Esbriet pirfenidone
tablet, coated
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:50242-123
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
PIRFENIDONE (PIRFENIDONE)
|
PIRFENIDONE
|
801 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
MICROCRYSTALLINE CELLULOSE
|
|
|
SILICON DIOXIDE
|
|
|
POVIDONE K30
|
|
|
CROSCARMELLOSE SODIUM
|
|
|
MAGNESIUM STEARATE
|
|
|
POLYVINYL ALCOHOL,
UNSPECIFIED
|
|
|
TITANIUM DIOXIDE
|
|
|
POLYETHYLENE GLYCOL 3350
|
|
|
TALC
|
|
|
FERRIC OXIDE RED
|
|
|
FERROSOFERRIC OXIDE
|
|
|
|
Product Characteristics
|
|
Color
|
BROWN (Grayish brown to brownish red)
|
Score
|
no score
|
|
Shape
|
OVAL
|
Size
|
20mm
|
|
Flavor
|
|
Imprint Code
|
PFD
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:50242-123-01
|
1 BOTTLE, PLASTIC in 1 CARTON
|
|
|
1
|
|
90 TABLET, COATED in 1 BOTTLE, PLASTIC
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA208780
|
01/11/2017
|
|
|
|
Labeler - Genentech, Inc. (080129000)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Roche S.p.A.
|
|
430351356
|
MANUFACTURE(50242-122, 50242-123), ANALYSIS(50242-122,
50242-123), PACK(50242-122, 50242-123), LABEL(50242-122, 50242-123)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
F. Hoffmann-La Roche Ltd
|
|
482242971
|
ANALYSIS(50242-122, 50242-123)
|
Revised: 10/2017
Genentech, Inc.
