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Esbriet

Generic Name: Pirfenidone
Class: Antifibrotic Agents
Chemical Name: 5-Methyl-1-phenyl-2(1H)-pyridinone
Molecular Formula: C12H11NO
CAS Number: 53179-13-8

Introduction

Antifibrotic agent; synthetic pyridone.1 2 3 5 7

Uses for Esbriet

Idiopathic Pulmonary Fibrosis

Treatment of idiopathic pulmonary fibrosis (IPF) (designated an orphan drug by FDA for this use).1 4

Esbriet Dosage and Administration

General

  • Monitor liver function tests prior to initiation, monthly for the first 6 months, and then every 3 months.1

Administration

Oral Administration

Administer orally 3 times daily with food.1

Administer at the same time every day; do not exceed 3 doses per day.1

If a dose is missed, take the next dose as soon as it is remembered; do not take 2 doses at the same time to make up for a missed dose.1

Dosage

Adults

Idiopathic Pulmonary Fibrosis
Oral

Recommended maintenance dosage: 801 mg (three 267-mg capsules) 3 times daily.1

Initial dosage titration upward over 2-week period: 267 mg (1 capsule) 3 times daily for 7 days, followed by 534 mg (two 267-mg capsules) 3 times daily for an additional 7 days, and then 801 mg (three 267-mg capsules) 3 times daily thereafter.1

Following treatment interruption of ≥14 days: Titrate dosage upward using the initial 2-week dosage titration regimen.1

Following treatment interruption of <14 days: Therapy can be resumed at dosage received prior to treatment interruption.1

Dosage Modification
Hepatic Toxicity

ALT or AST elevations >3 times but ≤5 times the ULN without symptoms or hyperbilirubinemia: May continue therapy at full dosage, temporarily interrupt therapy, or reduce dosage until liver function tests return to normal.1 May resume therapy and subsequently increase to full dosage as tolerated.1 Monitor patients carefully; discontinue other medications that could cause liver enzyme elevations; exclude other causes of such elevations.1

ALT or AST elevations >3 times but ≤5 times the ULN with symptoms or hyperbilirubinemia, or ALT or AST >5 times the ULN: Permanently discontinue therapy.1 (See Hepatic Toxicity under Cautions.)

Other Adverse Effects

If clinically important adverse reactions occur (i.e., GI effects such as nausea, diarrhea, dyspepsia, vomiting; photosensitivity reaction or rash), consider interruption of therapy or temporary dosage reduction until symptoms resolve.1 (See GI Effects and also see Photosensitivity under Cautions.)

Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes

If concomitant use with a potent CYP1A2 inhibitor (e.g., fluvoxamine) cannot be avoided, reduce pirfenidone dosage to 267 mg (1 capsule) 3 times daily.1

If concomitant use with the moderate CYP1A2 inhibitor ciprofloxacin (at a dosage of 750 mg twice daily) cannot be avoided, reduce pirfenidone dosage to 534 mg (two 267-mg capsules) 3 times daily.1 (See Drugs Affecting Hepatic Microsomal Enzymes under Interactions.)

Prescribing Limits

Adults

Idiopathic Pulmonary Fibrosis
Oral

2403 mg daily (801 mg [3 capsules] 3 times daily).1

Special Populations

Hepatic Impairment

No initial dosage adjustment required in patients with mild or moderate hepatic impairment (Child-Pugh class A or B); monitor closely for adverse effects.1

Not studied in patients with severe hepatic impairment (Child-Pugh class C); use not recommended.1

Renal Impairment

No initial dosage adjustment required in patients with mild, moderate, or severe renal impairment; monitor closely for adverse effects.1

Not studied in patients with end-stage renal disease requiring dialysis; use not recommended.1

Geriatric Patients

Dosage adjustment not required.1 (See Geriatric Use under Cautions.)

Cautions for Esbriet

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Hepatic Toxicity

Elevations in ALT and AST concentrations reported, including rare cases of hyperbilirubinemia.1 If abnormal liver function test results occur, temporary interruption, dosage reduction, or discontinuance of therapy may be necessary.1 (See Dosage Modification under Dosage and Administration.)

Perform liver function tests prior to initiation, monthly for the first 6 months, and then every 3 months thereafter.1

Photosensitivity

Photosensitivity reactions manifested as rash or other reactions reported.1 Most of these reactions occurred during the first 6 months following therapy initiation.1

Interruption of therapy and/or dosage reduction may be necessary in some patients.1 (See Dosage Modification under Dosage and Administration and see Advice to Patients.)

GI Effects

Nausea, diarrhea, dyspepsia, vomiting, GERD, and abdominal pain may occur.1 Adverse GI effects generally occur within first 3 months of therapy and decrease over time.1

Interruption of therapy and/or dosage reduction may be necessary in some patients.1 (See Dosage Modification under Dosage and Administration and see Advice to Patients.)

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

No overall differences in safety and efficacy relative to younger adults.1

Hepatic Impairment

Increased peak plasma concentrations and systemic exposure to pirfenidone occurred in patients with moderate hepatic impairment (Child-Pugh class B); not studied in patients with severe hepatic impairment (Child-Pugh class C).1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Increased systemic exposure in patients with mild to severe renal impairment (Clcr <30 to 80 mL/minute); not studied in patients with end-stage renal disease requiring dialysis.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Nausea, rash, abdominal pain, upper respiratory tract infection, diarrhea, fatigue, headache, dyspepsia, dizziness, vomiting, anorexia, GERD, sinusitis, insomnia, decreased weight, arthralgia.1

Interactions for Esbriet

Metabolized principally by CYP1A2 and, to a lesser extent, by CYP2C9, 2C19, 2D6, and 2E1.1

Has weak inhibitory potential on P-glycoprotein (P-gp) in vitro.1

Concentration-dependent inhibition of CYP2C9, 2C19, 1A2, 2D6, and 3A4 in vitro.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP1A2 inhibitors: Potential increased pirfenidone exposure.1 Avoid concomitant use or reduce pirfenidone dosage.1 (See Dosage Modification under Dosage and Administration.)

Moderate CYP1A2 inhibitors: Potential increased pirfenidone exposure; monitor patients closely during concomitant use.1 (See Specific Drugs under Interactions.)

Avoid concomitant use with agents or combination of agents that are potent or moderate inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved with pirfenidone metabolism (i.e., CYP2C9, 2C19, 2D6, 2E1).1

Specific Drugs

Drug

Interaction

Comments

Cigarette smoking

Decreased pirfenidone concentrations1

Advise patients to stop smoking prior to initiation of therapy and to avoid smoking during therapy1

Ciprofloxacin

Increased systemic exposure to pirfenidone following concomitant administration with ciprofloxacin 750 mg twice daily1

Ciprofloxacin 750 mg twice daily: If concomitant therapy cannot be avoided, reduce pirfenidone dosage to 534 mg (2 capsules) 3 times a day1

Ciprofloxacin 250–500 mg once daily: If concomitant therapy required, monitor patient closely1

Fluvoxamine

Increased systemic exposure to pirfenidone approximately fourfold in nonsmokers and sevenfold in smokers1

Discontinue fluvoxamine prior to initiation of pirfenidone; avoid concomitant use 1

If concomitant use cannot be avoided, reduce pirfenidone dosage to 267 mg (1 capsule) 3 times a day1

Monitor patients for adverse effects; consider discontinuance of pirfenidone as needed1

Nintedanib

Decreased systemic exposure to nintedanib8

No effect on pirfenidone pharmacokinetics8

Esbriet Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations achieved at a median of 0.5 hours (range: 0.5–4 hours) following oral administration.1

Absolute bioavailability not known.1

Food

Administration with food decreases systemic exposure by 16% and delays median time to peak plasma concentrations by 2.5 hours compared with the fasting state.1

Special Populations

Systemic exposure and peak plasma concentrations increased approximately 1.6- and 1.4-fold, respectively, in individuals with moderate hepatic impairment (Child-Pugh class B).1

Systemic exposure increased approximately 1.4-, 1.5-, and 1.2-fold in individuals with mild, moderate, and severe renal impairment, respectively.1

Distribution

Extent

Not known whether pirfenidone is distributed into human milk.1

Plasma Protein Binding

58% (mainly albumin).1

Elimination

Metabolism

Undergoes hepatic metabolism, principally by CYP1A2 (70–80%) and, to a lesser extent, by CYP2C9, 2C19, 2D6, and 2E1.1 7 Major metabolite 5-carboxy-pirfenidone expected to be pharmacologically inactive.1

Elimination Route

Approximately 80% excreted in urine within 24 hours, mainly as 5-carboxy-pirfenidone.1 7

Half-life

Approximately 3 hours.1

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).1

Actions

  • Precise mechanism of action in the treatment of IPF not fully elucidated; may be related to the drug's antifibrotic, anti-inflammatory, and antioxidant properties.1 7 10

  • Inhibits activation of transforming growth factor-β (TGF-β), a profibrotic, proinflammatory cytokine that plays a role in the differentiation of fibroblasts.6 7 10

  • Inhibits TGF-β-mediated proliferation of human lung fibroblasts and differentiation into myofibroblasts in vitro,7 a process which may lead to excessive collagen deposition and fibrosis in the lungs.6 7 12

  • Inhibits release of proinflammatory cytokines (e.g., IL-1β, IL-6, tumor necrosis factor [TNF]-α, platelet derived growth factor [PDGF]) in animal models and in vitro.7 10

  • Possesses antioxidant activity; shown to scavenge reactive oxygen species (ROS), including hydroxyl radicals and superoxide anions, in vitro.7

Advice to Patients

  • Importance of reading the manufacturer’s patient information prior to beginning therapy and each time the prescription is refilled.1

  • Importance of taking pirfenidone with food to reduce the incidence of adverse effects (e.g., nausea, dizziness).1

  • Importance of advising patients that if a dose is missed, to take the dose as soon as it is remembered; do not take 2 doses at the same time to make up for a missed dose.1 Do not take more than 3 doses per day.1

  • Risk of hepatotoxicity and importance of periodic liver function test monitoring.1 Importance of immediately reporting any manifestations of hepatotoxicity (e.g., jaundice, unusually dark or “tea-colored” urine, right upper quadrant pain, bleeding or bruising more easily than normal, lethargy).1

  • Risk of photosensitivity manifested as rash or other reactions.1 Importance of using sunscreen and protective clothing; limit exposure to sunlight, including sunlamps, during therapy.1 Importance of immediately reporting any symptoms of photosensitivity reaction or rash to a clinician.1

  • Risk of adverse GI effects (e.g., nausea, diarrhea, dyspepsia, vomiting, GERD, abdominal pain).1 Importance of contacting clinician if persistent adverse GI effects occur.1

  • Importance of advising cigarette smokers to avoid smoking during therapy because concentrations of the drug and efficacy may be reduced.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements as well as any concomitant illnesses (e.g., hepatic impairment).1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Pirfenidone

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

267 mg

Esbriet

InterMune

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Date published: December 02, 2015
Last reviewed: December 02, 2015
Date modified: February 08, 2016

References

1. InterMune, Inc. Esbriet (pirfenidone) capsules prescribing information. Brisbane, CA; 2014 Oct.

2. King TE, Bradford WZ, Castro-Bernardini S et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014; 370:2083-92. [PubMed 24836312]

3. Noble PW, Albera C, Bradford WZ et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011; 377:1760-9. [PubMed 21571362]

4. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2015 Jul 13.

5. Raghu G, Collard HR, Egan JJ et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011; 183:788-824. [PubMed 21471066]

6. Wolters PJ, Collard HR, Jones KD. Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol. 2014; 9:157-79. [PubMed 24050627]

7. Kim ES, Keating GM. Pirfenidone: a review of its use in idiopathic pulmonary fibrosis. Drugs. 2015; 75:219-30. [PubMed 25604027]

8. Ogura T, Taniguchi H, Azuma A et al. Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J. 2015; 45:1382-92. [PubMed 25504994]

9. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 022535Orig1s000: Summary review. From FDA website.

10. Roche Registration Limited. Esbrieti (pirfenidone) capsules. Annex I: Summary of product characteristics. Welwyn Garden City, United Kingtom. (undated)

12. King TE, Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet. 2011; 378:1949-61. [PubMed 21719092]

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