pirfenidone 267 MG Oral Capsule
DRUG INTERACTIONS
7 Moderate (e.g., ciprofloxacin) and strong inhibitors of CYP1A2 (e.g., fluvoxamine) increase systemic exposure of ESBRIET and may alter the adverse reaction profile of ESBRIET.
Discontinue fluvoxamine prior to administration of ESBRIET or reduce to one capsule 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 CYP1A 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 CYP1A 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.
7.2 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)] .
OVERDOSAGE
10 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.
DESCRIPTION
11 Each ESBRIET capsule contains 267 mg of pirfenidone, which belongs to the chemical class of pyridone.
ESBRIET is available as a white hard gelatin capsule for oral administration.
The chemical name of pirfenidone is 5-methyl-1-phenyl-2-1(H)-pyridone.
It has a molecular formula of C 12 H 11 NO and a molecular weight of 185.23.
The structural formula of pirfenidone is: 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.
Chemical Structure
CLINICAL STUDIES
14 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 (%DL CO ) 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 %DL CO were 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 Figure 1 Figure 1 Figure 1
HOW SUPPLIED
16 /STORAGE AND HANDLING ESBRIET is a white hard gelatin capsule; each capsule contains 267 mg of pirfenidone.
The cap of the capsule is printed with “InterMune ® ” and “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.
Bottle for a 30-day supply Bottle containing 270 capsules and closed with a child- resistant closure NDC 64116-121-01 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 64116-121-02 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) NDC 64116-121-03 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.
GERIATRIC USE
8.5 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.
DOSAGE FORMS AND STRENGTHS
3 Capsules: 267 mg, white, hard gelatin capsules printed with “InterMune ® ” and “267 mg” on the cap of the capsule in brown ink.
Capsules: 267 mg ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action The mechanism of action of pirfenidone in the treatment of IPF has not been established.
INDICATIONS AND USAGE
1 ESBRIET is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).
ESBRIET is a pyridone indicated for the treatment of idiopathic pulmonary fibrosis (IPF).
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness of ESBRIET in pediatric patients have not been established.
PREGNANCY
8.1 Pregnancy Teratogenic Effects: Pregnancy Category C .
There are no adequate and well-controlled studies of ESBRIET in pregnant women.
Pirfenidone was not teratogenic in rats and rabbits.
Because animal reproduction studies are not always predictive of human response, ESBRIET should be used during pregnancy only if the benefit outweighs the risk to the patient.
A fertility and embryo-fetal development study with rats and an embryo-fetal development study with rabbits that received oral doses up to 3 and 2 times, respectively, the maximum recommended daily dose (MRDD) in adults (on mg/m 2 basis at maternal doses up to 1000 and 300 mg/kg/day, 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, 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 dose of 1000 mg/kg/day).
NUSRING MOTHERS
8.3 Nursing Mothers A study with radio-labeled pirfenidone in rats has shown that pirfenidone or its metabolites are excreted in milk.
It is not known whether ESBRIET is excreted in human milk.
Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue ESBRIET, taking into account the importance of the drug to the mother.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Elevated liver enzymes: ALT, AST, and bilirubin elevations have occurred with ESBRIET.
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 ESBRIET.
Avoid exposure to sunlight and sunlamps.
Wear sunscreen and protective clothing daily.
Temporary dosage reductions or discontinuations may be required.
( 5.2 ) Gastrointestinal disorders: Nausea, vomiting, diarrhea, dyspepsia, gastro-esophageal reflux disease, and abdominal pain have occurred with ESBRIET.
Temporary dosage reductions or discontinuations may be required.
( 5.3 ) 5.1 Elevated Liver Enzymes Increases in ALT and AST >3 × ULN have been reported in patients treated with ESBRIET.
Rarely 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)].
5.2 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)] .
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 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)] .
INFORMATION FOR PATIENTS
17 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.
DOSAGE AND ADMINISTRATION
2 Recommended dosage: 801 mg (three capsules) three times daily taken with food.
( 2 ) Upon initiation of treatment, the daily dosage should be titrated to the full dosage of nine capsules per day over a 14-day period as follows: Treatment days Dosage Days 1 through 7 1 capsule three times a day with meals Days 8 through 14 2 capsules three times a day with meals Days 15 onward 3 capsules three times a day with meals Consider temporary dosage reduction, treatment interruption, or discontinuation for management of adverse reactions.
( 2.3 , 5.1 , 5.2 , 5.3 ) Prior to treatment, conduct liver function tests.
( 2.1 ) 2.1 Testing Prior to ESBRIET Administration Conduct liver function tests prior to initiating treatment with ESBRIET [see Warnings and Precautions (5.1)] .
2.2 Recommended Dosage The recommended daily maintenance dosage of ESBRIET is 801 mg (three 267 mg capsules) three times a day with food for a total of 2403 mg/day.
Doses should be taken at the same time each day.
Upon initiation of treatment, titrate to the full dosage of nine capsules per 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 1 capsule three times a day with food Days 8 through 14 2 capsules three times a day with food Days 15 onward 3 capsules three times a day with food Dosages above 2403 mg/day (9 capsules per day) are not recommended for any patient.
2.3 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.
2.4 Dosage Modification due to Drug Interactions Strong CYP1A2 Inhibitors (e.g., fluvoxamine, enoxacin) Reduce ESBRIET to one capsule three times a day.
Moderate CYP1A2 Inhibitors (e.g., ciprofloxacin) With use of ciprofloxacin at a dosage of 750 mg twice daily, reduce ESBRIET to two capsules three times a day.