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Retrospective CV & Bleeding Risk

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Cardiovascular and bleeding risk factors in Esbriet clinical trials: retrospective analysis
CV and bleeding events were evaluated in 1247 patients with IPF in a post hoc analysis of three phase 3 trials with Esbriet vs placebo

Cardiovascular and bleeding risk factors in Esbriet® (pirfenidone) clinical trials: retrospective analysis22

Study design

  • A retrospective blinded review of AE preferred terms to identify MACE-plus and bleeding events (up to 28 days post-treatment) in three randomized, placebo-controlled phase 3 trials of pirfenidone (ASCEND, CAPACITY 004, and CAPACITY 006)*
  • Patients with unstable or deteriorating cardiac disease within 6 months before enrollment were ineligible for phase 3 trials of pirfenidone
  • MACE-plus is defined as major adverse cardiac events–plus, which included non-fatal myocardial infarction, non-fatal stroke, acute coronary syndrome, and any CV death due to myocardial infarction, sudden cardiac death, heart failure, stroke, CV procedures (immediate), or other CV causes (eg, pulmonary embolism, peripheral arterial disease)

Cardiovascular and bleeding risk factors at baseline22

Medication Esbriet
[n=623]		 Placebo
[n=624]
Baseline CV risk factors† 92.1% 92.3%
Patients with ≥3 CV risk factors† 45.9% 44.9%
Smoking (former or current)‡ 66.5% 64.2%
Hypertension 49.4% 54.5%
Obesity§ 45.7% 42.9%
Hypercholesterolemia 24.4% 22.4%
Hyperlipidemia 23.1% 22.1%
Diabetes, type 1 or 2 21.5% 19.2%
Sleep apnea 14.6% 15.2%
Coronary artery disease 15.6% 15.7%
Myocardial infarction 5.1% 5.3%
Atrial fibrillation 4.7% 4.6%
Angina pectoris 3.0% 1.9%
Deep vein thrombosis 2.1% 2.2%
Pulmonary embolism 1.3% 1.0%

Most common concomitant CV medications in Esbriet clinical trials22

Medication Esbriet
[n=623]		 Placebo
[n=624]
Lipid-modifying agents 60.7% 59.9%
Antithrombotic agents 51.2% 57.2%

Anticoagulation agents

 10.6% 13.8%

Antiplatelet agents

 47.2% 50.6%
RAAS inhibitors 34.8% 42.6%
Beta-blockers 24.7% 25.3%
Diuretics 20.9% 22.4%
Antidiabetic agents 21.0% 20.4%
Calcium-channel blockers 17.2% 17.9%
Other antihypertensive agents 2.4% 2.6%

CV=cardiovascular; RAAS=renin-angiotensin-aldosterone system; BMI=Body Mass Index.
*MACE-plus events were adjudicated by an external academic cardiologist who was blinded to the treatment assignment.
†CV risk factors, not including age or sex, were defined as smoking, hypertension, hypercholesterolemia, hyperlipidemia, diabetes, sleep apnea, and obesity (BMI ≥30).
‡The ASCEND study did not enroll current smokers.
§Obesity was based on the World Health Organization classification of BMI.

CV and bleeding events were evaluated in 1247 patients with IPF in a post hoc analysis of three phase 3 trials with Esbriet vs placebo22

Study Limitations

  • This is a post hoc analysis; therefore, the findings may need to be interpreted with caution
  • This analysis is limited to a selected IPF clinical trial population. The occurrence of CV events might be higher in a broader group of patients with IPF
  • Concomitant use of warfarin and heparin was limited in this cohort

Percent of patients with treatment-emergent MACE-plus events22

MACE events chart

Percent of patients with treatment-emergent bleeding events22

Bleeding events chart

Adapted from Advances in Therapy. Glassberg MK, Nathan SD, Lin C-Y, et al. 2019;36(10):2910-2926.

||Other includes: GI hemorrhage, hemorrhagic stroke, pulmonary alveolar hemorrhage, vaginal hemorrhage, catheter-site hemorrhage, extravasation blood, urinary tract hemorrhage, hemorrhoidal hemorrhage, injection-site hemorrhage, large intestinal hemorrhage, peptic ulcer hemorrhage, postmenopausal hemorrhage, pulmonary hemorrhage.

Side Effects

Some people may experience side effects when taking Esbriet

Learn more
NEXT: Important Safety Information

Important Safety Information and Indication

Indication

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

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.

Severe Cutaneous Adverse Reactions: Severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported in association with the use of Esbriet in the post-marketing setting. If signs or symptoms of SCAR occur, interrupt Esbriet treatment until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, permanently discontinue Esbriet.

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, decreased appetite, dyspepsia, dizziness, vomiting, 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.

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