Esbriet® (pirfenidone)

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Indication

Esbriet® (pirfenidone) is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).

Select Important Safety Information

Elevated liver enzymes and drug-induced liver injury (DILI): DILI has been observed with Esbriet. In the postmarketing period, non-serious and serious cases of DILI, including severe liver injury with fatal outcome, have been reported. Patients treated with Esbriet had a higher incidence of ALT and/or AST elevations of ≥3x ULN (3.7%) compared with placebo patients (0.8%). Increases in ALT and AST ≥3x ULN were reversible with dose modification or treatment discontinuation.

Conduct liver function tests (ALT, AST, and bilirubin) prior to the initiation of therapy with Esbriet, monthly for the first 6 months, every 3 months thereafter, and as clinically indicated. Measure liver function 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.

Photosensitivity reaction or rash: Patients treated with Esbriet had a higher incidence of photosensitivity reactions (9%) vs placebo (1%). Patients should avoid or minimize exposure to sunlight and sunlamps, regularly use sunscreen (SPF 50 or higher), wear clothing that protects against sun exposure, and avoid concomitant medications that cause photosensitivity. Dosage reduction or discontinuation may be necessary.

Gastrointestinal (GI) disorders: Patients treated with Esbriet had a higher incidence of nausea, diarrhea, dyspepsia, vomiting, gastroesophageal reflux disease (GERD), and abdominal pain. GI events required dose reduction or interruption in 18.5% of 2403 mg/day Esbriet-treated patients, compared with 5.8% of placebo patients; 2.2% of 2403 mg/day Esbriet-treated patients discontinued treatment due to a GI event, vs 1.0% of placebo patients. The most common (>2%) GI events leading to dosage reduction or interruption were nausea, diarrhea, vomiting, and dyspepsia. Dosage modification may be necessary.

Adverse reactions: The most common adverse reactions (≥10%) were nausea, rash, abdominal pain, upper respiratory tract infection, diarrhea, fatigue, headache, dyspepsia, dizziness, vomiting, anorexia, GERD, sinusitis, insomnia, weight decreased, and arthralgia.

Drug Interactions:

CYP1A2 inhibitors: Concomitant use of Esbriet and strong CYP1A2 inhibitors (e.g., fluvoxamine) is not recommended, as CYP1A2 inhibitors increase systemic exposure of Esbriet. If discontinuation of the CYP1A2 inhibitor prior to starting Esbriet is not possible, dosage reduction of Esbriet is recommended. Monitor for adverse reactions and consider discontinuation of Esbriet.

Concomitant use of ciprofloxacin (a moderate CYP1A2 inhibitor) at the dosage of 750 mg BID and Esbriet are not recommended. If this dose of ciprofloxacin cannot be avoided, dosage reductions of Esbriet are recommended, and patients should be monitored.

Moderate or strong inhibitors of both CYP1A2 and other CYP isoenzymes involved in the metabolism of Esbriet should be avoided during treatment.

CYP1A2 inducers: Concomitant use of Esbriet and strong CYP1A2 inducers should be avoided, as CYP1A2 inducers may decrease the exposure and efficacy of Esbriet.

Specific Populations:

Mild to moderate hepatic impairment: Esbriet should be used with caution in patients with Child Pugh Class A and B. Monitor for adverse reactions and consider dosage modification or discontinuation of Esbriet as needed.

Severe hepatic impairment: Esbriet is not recommended for patients with Child Pugh Class C. Esbriet has not been studied in this patient population.

Mild (CLcr 50–80 mL/min), moderate (CLcr 30–50 mL/min), or severe (CLcr <30 mL/min) renal impairment: Esbriet should be used with caution. Monitor for adverse reactions and consider dosage modification or discontinuation of Esbriet as needed.

End-stage renal disease requiring dialysis: Esbriet is not recommended. Esbriet has not been studied in this patient population.

Smokers: Smoking causes decreased exposure to Esbriet which may affect efficacy. Instruct patients to stop smoking prior to treatment and to avoid smoking when on Esbriet.

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch or to Genentech at 1-888-835-2555.

Please see full Prescribing Information for additional Important Safety Information.

 

About Esbriet

Esbriet® (pirfenidone) is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).

Esbriet can help preserve more lung function by reducing lung function decline.

Trial Design

Esbriet was rigorously analyzed in three phase 3 trials

Esbriet was evaluated in 1247 patients with IPF in three phase 3 trials.1
The efficacy of Esbriet was evaluated in three phase 3, randomized, double-blind, placebo-controlled, multicenter trials1-3

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  • Adult patients were enrolled who had a clinical and radiographic diagnosis of IPF (with or without accompanying surgical biopsy), without evidence or suspicion of an alternative diagnosis for interstitial lung disease1
  • Study drug was administered with food in 3 equally divided doses and gradually increased to full dose over 2 weeks2,3

Esbriet was studied across a range of patients with IPF

Clinical trials included patients with IPF with a range of clinical characteristics, select comorbidities, and concomitant medications.4

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%FVC=percent predicted forced vital capacity; %DLco=percent predicted diffusing capacity of lung for carbon monoxide; FVC=forced vital capacity.

*Prevalence of comorbidities occurred in ≥15% of enrolled patients across all trials (N=1247).

Medications listed are commonly administered for select comorbidities.

Lung Function

Esbriet preserves more lung function for patients with IPF

Esbriet had a significant impact on lung function vs placebo1,2

ASCEND: Significant difference in maintaining baseline lung function for Esbriet vs placebo at 52 weeks (P<0.001)

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Rank ANCOVA with lowest rank imputation for missing data due to death. Patients who died were counted in the ≥10% decline category.1,4

  • No decline or an increase in lung function is defined as a ≥0% decline in %FVC from baseline at 52 weeks1

Disease progression as measured by FVC decline was considered a high-value, patient-important outcome [ATS/ERS/JRS/ALAT Clinical Practice Guideline According to ATS guideline]6

ASCEND: Significant difference in reducing risk of lung function decline for Esbriet vs placebo at 52 weeks (P<0.001)


Rank ANCOVA with lowest rank imputation for missing data due to death. Patients who died were counted in the ≥10% decline category.1,4

  • Meaningful decline in lung function is defined as a ≥10% decline in %FVC at 52 weeks1

According to ATS guidelines, ≥10% FVC decline is an established measure of IPF disease progression and may be predictive of mortality10

Esbriet delays disease progression

Esbriet delayed progression of IPF vs placebo through a sustained impact on reducing lung function decline1,2,4

ASCEND: Mean change from baseline in FVC vs placebo over 52 weeks

Click to expand image

P value is from rank ANCOVA on the % change in FVC volume.Impact of Esbriet on FVC volume was assessed at week 13, week 26, and week 39, with the primary endpoint at week 521,2,4

Change in FVC over time is a widely accepted assessment of disease progression in IPF, with even small declines believed to be clinically important7,8

Significant effect on lung function for up to 72 weeks with Esbriet

Significantly fewer patients on Esbriet had a meaningful decline in lung function (≥10% decline in %FVC) vs placebo3,14

CAPACITY 004: Significant difference in reducing risk of lung function decline as measured by %FVC for Esbriet vs placebo at 72 weeks (P=0.001)§

Click to expand image

§P value is from Cochran-Mantel-Haenszel (CMH) row mean scores test.

  • In CAPACITY 004, patients on Esbriet also maintained significantly more lung function vs placebo, as measured by mean change in FVC (157 mL), P=0.0041,5
  • In CAPACITY 006, no statistically significant difference vs placebo in change in %FVC or decline in FVC volume from baseline to 72 weeks was observed1,3

*Recognize that different choices will be appropriate for individual patients and that you must help each patient arrive at a management decision consistent with his or her values and preferences.

Exploratory Survival Analysis

Esbriet achieved a numerical difference in all-cause mortality in three phase 3 trials1,4

No statistically significant difference over the study and follow-up period (up to 120 weeks for available patients)1,4

ASCEND, CAPACITY 004, and CAPACITY 006 exploratory survival analysis vs placebo

Cumulative risk of all-cause mortality through study and follow-up (120 weeks)1,4

HR=hazard ratio; CI=confidence interval.

Multinational, randomized, double-blind, placebo-controlled studies vs placebo1,2

  • Primary FVC endpoint was measured at 52 weeks for ASCEND and at 72 weeks for CAPACITY 004 and CAPACITY 0061
  • All-cause mortality was assessed over the study duration and available follow-up, irrespective of cause of death and whether patients continued treatment after study primary endpoint1
Safety and Tolerability Profile of Esbriet

SAFETY: Safety data were obtained from 1247 patients in 3 randomized, controlled trials1

*Includes abdominal pain, upper abdominal pain, abdominal distension, and stomach discomfort.

  • The most common adverse reactions (>1%) leading to discontinuation were rash and nausea
  • In clinical trials, elevated liver enzymes, photosensitivity reactions, and gastrointestinal disorders have been reported with Esbriet

TOLERABILITY: Some adverse reactions with Esbriet occurred early and/or decreased over time1

 

Long-term, open-label, phase 3 extension study

Follow-up safety data available for up to 6.7 years9

  • In a long-term, open-label extension of the phase 3 studies, 1058 patients with IPF were exposed to Esbriet for a median of 88 weeks/1.7 years (range, >0 to 349 weeks/6.7 years) with the primary objective of obtaining additional safety data for Esbriet 2403 mg/day
  • 40.4% (n=427) completed the study, with an overall discontinuation rate of 59.2% (n=626)
    • The most frequent adverse drug reactions were nausea (21.6%), diarrhea (12.3%), and rash (11.6%)
    • The most common treatment-emergent serious adverse events were IPF (21.7%) and pneumonia (8.5%)
    • 42% (n=444) discontinued due to treatment-emergent adverse events, including 16.8% (n=178) who discontinued due to IPF
  • Care should be exercised when interpreting open-label results due to the inability to minimize bias. The data represented are not designed to establish the long-term safety or tolerability profile for Esbriet

Adverse drug reactions are defined as adverse events judged by the investigator as possibly or probably related to pirfenidone.

Treatment-emergent adverse events are defined as all events that occurred from the first dose of pirfenidone through 28 days after the last dose in the long-term, open-label, phase 3 extension study.

Dosing

Options to start and maintain patients on Esbriet

Start patients with Esbriet 267 mg tablets1

  • Conduct liver function tests prior to initiating treatment with Esbriet and periodically thereafter
  • Titrate patients to the recommended daily dosage of three 267 mg tablets or capsules TID with meals over a 14-day period

Maintain patients on Esbriet with just one 801 mg tablet 3 times a day1

  • After the full dose of three 267 mg tablets or capsules TID is well tolerated, transition patients to one 801 mg tablet TID for a maintenance option with fewer pills per day

TID=three times a day.
*Tablets are not shown at actual size.

  • Esbriet tablets and capsules are bioequivalent

Dosing recommendations1

  • Esbriet should be taken with meals at the same time each day to help decrease side effects such as nausea and dizziness
  • Dose modification due to drug interactions may be necessary in patients taking strong or moderate CYP1A2 inhibitors
  • Dosages above 2403 mg/day are not recommended for any patient

 

Transition your patients to Esbriet 801 mg tablets in 3 steps

Your patients may be ready for Esbriet 801 mg tablets when:1

  • Tolerating full dose (three 267 mg tablets or capsules TID)
  • Interested in maintenance dose with fewer pills

3 steps to transition your patients

  1. Complete a new Statement of Medical Necessity (SMN) form and check the “Esbriet 801 mg” box
  2. Fax the SMN form to Esbriet Access Solutions at 1-844-372-7444
  3. New 801 mg prescription will be filled as soon as possible by the appropriate specialty pharmacy

If your patient’s prior authorization (PA) is still valid, another PA is likely not needed. Contact Esbriet Access Solutions at 1-844-ESBRIET (1-844-372-7438) or visit Genentech-Access.com/Esbriet for more information.

Reminders for your patients

  • Talk to their specialty pharmacy about when to fill their 801 mg prescriptions
  • Always take Esbriet with meals
  • Take Esbriet only as prescribed

 

Flexible dosing with Esbriet 267 mg may help manage potential adverse reactions

Dose modification, interruption, or discontinuation may be appropriate to help manage side effects (eg, elevated liver enzymes, gastrointestinal events, photosensitivity reactions or rash)1

ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal.

Reinitiating treatment following treatment interruptions:1

  • Patients who miss 14 or more days of Esbriet should reinitiate treatment by repeating the initial 2-week titration regimen
  • For a treatment interruption of fewer than 14 days, the dosage taken prior to the interruption can be resumed

Important Safety Information

Elevated liver enzymes and drug-induced liver injury (DILI): DILI has been observed with Esbriet. In the postmarketing period, non-serious and serious cases of DILI, including severe liver injury with fatal outcome, have been reported. Patients treated with Esbriet had a higher incidence of ALT and/or AST elevations of ≥3x ULN (3.7%) compared with placebo patients (0.8%). Increases in ALT and AST ≥3x ULN were reversible with dose modification or treatment discontinuation.

Conduct liver function tests (ALT, AST, and bilirubin) prior to the initiation of therapy with Esbriet, monthly for the first 6 months, every 3 months thereafter, and as clinically indicated. Measure liver function 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.

Photosensitivity reaction or rash: Patients treated with Esbriet had a higher incidence of photosensitivity reactions (9%) vs placebo (1%). Patients should avoid or minimize exposure to sunlight and sunlamps, regularly use sunscreen (SPF 50 or higher), wear clothing that protects against sun exposure, and avoid concomitant medications that cause photosensitivity. Dosage reduction or discontinuation may be necessary.

Gastrointestinal (GI) disorders: Patients treated with Esbriet had a higher incidence of nausea, diarrhea, dyspepsia, vomiting, gastroesophageal reflux disease (GERD), and abdominal pain. GI events required dose reduction or interruption in 18.5% of 2403 mg/day Esbriet-treated patients, compared with 5.8% of placebo patients; 2.2% of 2403 mg/day Esbriet-treated patients discontinued treatment due to a GI event, vs 1.0% of placebo patients. The most common (>2%) GI events leading to dosage reduction or interruption were nausea, diarrhea, vomiting, and dyspepsia. Dosage modification may be necessary.

Adverse reactions: The most common adverse reactions (≥10%) were nausea, rash, abdominal pain, upper respiratory tract infection, diarrhea, fatigue, headache, dyspepsia, dizziness, vomiting, anorexia, GERD, sinusitis, insomnia, weight decreased, and arthralgia.

Drug Interactions:

CYP1A2 inhibitors: Concomitant use of Esbriet and strong CYP1A2 inhibitors (e.g., fluvoxamine) is not recommended, as CYP1A2 inhibitors increase systemic exposure of Esbriet. If discontinuation of the CYP1A2 inhibitor prior to starting Esbriet is not possible, dosage reduction of Esbriet is recommended. Monitor for adverse reactions and consider discontinuation of Esbriet.

Concomitant use of ciprofloxacin (a moderate CYP1A2 inhibitor) at the dosage of 750 mg BID and Esbriet are not recommended. If this dose of ciprofloxacin cannot be avoided, dosage reductions of Esbriet are recommended, and patients should be monitored.

Moderate or strong inhibitors of both CYP1A2 and other CYP isoenzymes involved in the metabolism of Esbriet should be avoided during treatment.

CYP1A2 inducers: Concomitant use of Esbriet and strong CYP1A2 inducers should be avoided, as CYP1A2 inducers may decrease the exposure and efficacy of Esbriet.

Specific Populations:

Mild to moderate hepatic impairment: Esbriet should be used with caution in patients with Child Pugh Class A and B. Monitor for adverse reactions and consider dosage modification or discontinuation of Esbriet as needed.

Severe hepatic impairment: Esbriet is not recommended for patients with Child Pugh Class C. Esbriet has not been studied in this patient population.

Mild (CLcr 50–80 mL/min), moderate (CLcr 30–50 mL/min), or severe (CLcr <30 mL/min) renal impairment: Esbriet should be used with caution. Monitor for adverse reactions and consider dosage modification or discontinuation of Esbriet as needed.

End-stage renal disease requiring dialysis: Esbriet is not recommended. Esbriet has not been studied in this patient population.

Smokers: Smoking causes decreased exposure to Esbriet which may affect efficacy. Instruct patients to stop smoking prior to treatment and to avoid smoking when on Esbriet.

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch or to Genentech at 1-888-835-2555.

Please see full Prescribing Information for additional Important Safety Information.

 

References

  1. Esbriet Prescribing Information. Genentech, Inc. July 2019.
  2. King TE Jr, Bradford WZ, Castro-Bernardini S, et al; for the ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis [published correction appears in N Engl J Med.2014;371(12):1172]. N Engl J Med. 2014;370(22):2083–2092.
  3. Noble PW, Albera C, Bradford WZ, et al; for the CAPACITY Study Group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. 2011;377(9779):1760–1769.
  4. Data on file. Genentech, Inc. 2019.
  5. Lee AS, Mira-Avendano I, Ryu JH, Daniels CE. The burden of idiopathic pulmonary fibrosis: an unmet public health need. Respir Med.2014;108(7):955–967.
  6. Raghu G, Rochwerg B, Zhang Y, et al; ATS, ERS, JRS, and ALAT. An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline [published correction appears in Am J Respir Crit Care Med.2015;192(5):644]. Am J Respir Crit Care Med. 2015;192(2):e3–e19.
  7. Zappala CJ, Latsi PI, Nicholson AG, et al. Marginal decline in forced vital capacity is associated with a poor outcome in idiopathic pulmonary fibrosis. Eur Respir J.2010;35(4):830–835.
  8. du Bois RM, Weycker D, Albera C, et al. Forced vital capacity in patients with idiopathic pulmonary fibrosis: test properties and minimal clinically important difference. Am J Respir Crit Care Med.2011;184(12):1382–1389.
  9. Costabel U, Albera C, Lancaster LH, et al. An open-label study of the long-term safety of pirfenidone in patients with idiopathic pulmonary fibrosis (RECAP). Respiration. 2017;94(5):408–415.
  10. Raghu G, Collard HR, Egan JJ, et al; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788–824.

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