Pirfenidone
Medically reviewed on Sep 10, 2018
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Esbriet: 267 mg
Tablet, Oral:
Esbriet: 267 mg, 801 mg
Brand Names: U.S.
· Esbriet
Pharmacologic Category
· Anti-inflammatory Agent
· Antifibrotic Agent
Pharmacology
Precise mechanisms of action have not been fully elucidated; however, pirfenidone may exert antifibrotic properties by decreasing fibroblast proliferation and the production of fibrosis-associated proteins and cytokines; may decrease the formation and accumulation of extracellular matrix (ie, collagen) in response to transforming growth factor-beta and platelet derived growth factor. Pirfenidone is also believed to exert anti-inflammatory properties by decreasing the accumulation of inflammatory cells resulting from a variety of stimuli.
Distribution
~59 to 71 L
Metabolism
Hepatic primarily via CYP1A2 and to a lesser extent via CYP2C9, 2C19, 2D6, and 2E1; major metabolite (5-carboxy-pirfenidone) is inactive
Excretion
Urine (~80%; >99% as metabolite)
Time to Peak
Plasma: Median: 0.5 hours (fasting); 3 hours (with food)
Half-Life Elimination
~3 hours
Protein Binding
Mean: 58% (primarily to albumin)
Special Populations: Renal Function Impairment
Systemic exposure (AUC0 to ∞) increased ~1.4, 1.5, and 1.2-fold in mild, moderate, and severe renal impairment, respectively. The corresponding AUC0 to ∞ of 5-carboxy-pirfenidone increased 1.7, 3.4, and 5.6-fold. The renal clearance of 5-carboxy-pirfenidone decreased significantly in patients with moderate to severe impairment.
Special Populations: Hepatic Function Impairment
In patients with moderate impairment (Child Pugh class B), mean exposure, AUC0 to ∞ and Cmax increased ~1.6- and ~1.4-fold in moderate hepatic impairment, respectively.
Use: Labeled Indications
Idiopathic pulmonary fibrosis: Treatment of idiopathic pulmonary fibrosis (IPF)
Contraindications
There are no contraindications listed in the manufacturer’s labeling.
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to pirfenidone or any component of the formulation; history of angioedema with pirfenidone; concomitant use of fluvoxamine; severe hepatic impairment or end-stage liver disease; severe renal impairment (CrCl <30 mL/minute) or end-stage renal disease (ESRD) requiring dialysis.
Dosing: Adult
Idiopathic pulmonary fibrosis (IPF): Oral:
Days 1 to 7: 267 mg 3 times daily (total dose: 801 mg/day)
Days 8 to 14: 534 mg 3 times daily (total dose: 1,602 mg/day)
Day 15 and thereafter: 801 mg 3 times daily (total dose: 2,403 mg/day). Maximum dose: 2,403 mg/day.
Reinitiation of therapy following interruption: If interruption <14 consecutive days, may reinitiate therapy at previous daily dose without retitration; if interruption ≥14 consecutive days, reinitiate therapy with the initial 2-week titration period up to recommended daily dose.
Dosage adjustment for concomitant therapy:
Strong CYP1A2 inhibitors (eg, fluvoxamine): Reduce pirfenidone to 267 mg 3 times daily (total dose: 801 mg/day).
Moderate CYP1A2 inhibitors (eg, ciprofloxacin): Reduce pirfenidone to 534 mg 3 times daily (total dose: 1,602 mg/day) when used concomitantly with ciprofloxacin 1,500 mg/day
Dosing: Geriatric
Refer to adult dosing.
Dosing: Renal Impairment
Mild to severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling. Use with caution; consider dose modification or discontinuation as needed.
ESRD requiring dialysis: Use is not recommended (has not been studied).
Dosing: Hepatic Impairment
Mild to moderate impairment (Child-Pugh class A and B): There are no dosage adjustments provided in the manufacturer’s labeling. Use with caution; consider dose modification or discontinuation as needed.
Severe impairment (Child-Pugh class C): Use is not recommended (has not been studied).
Dosing: Adjustment for Toxicity
Gastrointestinal (eg, nausea, diarrhea, dyspepsia, vomiting): There are no specific dosage adjustments provided in the manufacturer’s labeling; however, consider temporary dosage reduction and/or therapy interruption to allow for resolution of symptoms.
Hepatic:
ALT/AST >3 to ≤5 x ULN (without hyperbilirubinemia): Rule out alternative causes and discontinue potentially confounding medications. As clinically appropriate, may continue current dose, may reduce dose (specific dosing reductions are not provided in manufacturer’s labeling), or may temporarily discontinue therapy. Once aminotransferase elevations have resolved, may be re-titrated to the recommended daily dose. Monitor LFTs closely thereafter.
ALT/AST >3 to ≤5 x ULN with hyperbilirubinemia or symptoms: Discontinue therapy promptly and do not reinitiate.
ALT/AST >5 x ULN (regardless of serum bilirubin concentrations): Discontinue therapy promptly and do not reinitiate.
Photosensitivity reaction or rash: There is no specific dosage adjustment provided in the manufacturer’s labeling; however, consider temporary dosage reduction and/or therapy interruption to allow for resolution of symptoms.
Administration
Oral: Administer with food at the same time each day.
Dietary Considerations
Take with food to decrease frequency of dizziness or nausea. Avoid grapefruit juice.
Storage
Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).
Drug Interactions
Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates (High risk with Inhibitors). Monitor therapy
Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Avoid combination
Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Monitor therapy
Cannabis: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Monitor therapy
Ciprofloxacin (Systemic): May increase the serum concentration of Pirfenidone. Management: With ciprofloxacin doses of 1,500 mg/day, the pirfenidone dose should be reduced to 1,602 mg daily (ie, 534 mg three times a day). With lower daily doses of ciprofloxacin, use pirfenidone with caution. Consider therapy modification
CYP1A2 Inducers (Moderate): May decrease the serum concentration of Pirfenidone. Monitor therapy
CYP1A2 Inhibitors (Moderate): May increase the serum concentration of Pirfenidone. Management: Use any such combination with caution and close monitoring for pirfenidone toxicity. Avoid the use of pirfenidone with moderate CYP1A2 inhibitors whenever CYP2C9, 2C19, 2C6, or 2E1 is also inhibited (either by the CYP1A2 inhibitor or by a third drug). Consider therapy modification
CYP1A2 Inhibitors (Strong): May increase the serum concentration of Pirfenidone. Management: See full monograph for specific recommendations. Canadian product labeling specifically lists the use of pirfenidone with fluvoxamine as contraindicated. Consider therapy modification
Cyproterone: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers).Monitor therapy
Grapefruit Juice: May increase the serum concentration of Pirfenidone. Management: Consider advising patients to limit or avoid grapefruit juice consumption during treatment with pirfenidone. Canadian product labeling states that grapefruit juice should be avoided during pirfenidone treatment. Monitor therapy
Nintedanib: Pirfenidone may decrease the serum concentration of Nintedanib. Monitor therapy
Obeticholic Acid: May increase the serum concentration of CYP1A2 Substrates (High risk with Inhibitors).Monitor therapy
Peginterferon Alfa-2b: May increase the serum concentration of CYP1A2 Substrates (High risk with Inhibitors). Monitor therapy
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy
Teriflunomide: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers).Monitor therapy
Vemurafenib: May increase the serum concentration of CYP1A2 Substrates (High risk with Inhibitors). Management: Consider alternatives to such combinations whenever possible, particularly if the CYP1A2 substrate has a relatively narrow therapeutic index. Consider therapy modification
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy
Adverse Reactions
>10%:
Central nervous system: Fatigue (22% to 26%), headache (10% to 22%), dizziness (9% to 18%)
Dermatologic: Skin rash (29% to 30%; Japanese patients: 9%), skin photosensitivity (9% to 12%; Japanese patients: 51%)
Gastrointestinal: Nausea (33% to 36%), diarrhea (22% to 26%), abdominal pain (5% to 24%), dyspepsia (17% to 19%), anorexia (9% to 13%), vomiting (9% to 13%), gastroesophageal reflux disease (6% to 11%)
Respiratory: Upper respiratory tract infection (3% to 27%), sinusitis (1% to 11%)
≥3% to 10%:
Central nervous system: Insomnia (4% to 10%), noncardiac chest pain (1% to 5%), drowsiness (3%)
Dermatologic: Pruritus (4% to 8%), macular eruption (4%), sunburn (4%), erythema (3%)
Endocrine & metabolic: Weight loss (6% to 10%), increased gamma-glutamyl transferase (5%), hot flash (3%)
Gastrointestinal: Abdominal distension (9%), decreased appetite (8%), abdominal distress (3% to 8%), dysgeusia (1% to 6%), flatulence (5%)
Hepatic: Increased serum ALT (4%), increased serum transaminases (ALT and AST; ≥3 x ULN: 4%)
Neuromuscular & skeletal: Arthralgia (1% to 10%), weakness (6%)
Respiratory: Dyspnea (4%)
≥1% to <3%:
Central nervous system: Lethargy, malaise, paresthesia
Cardiovascular: Angina pectoris
Dermatologic: Desquamation, erythematous rash, hyperhidrosis, maculopapular rash, urticaria, xeroderma
Endocrine & metabolic: Dyslipidemia, fluid retention, gout, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hypokalemia, hyponatremia, increased lactate dehydrogenase, vitamin D deficiency
Gastrointestinal: Frequent bowel movements, gastritis, increased appetite
Genitourinary: Urinary tract infection, vaginal infection
Hepatic: Abnormal hepatic function tests
Infection: Influenza
Neuromuscular & skeletal: Increased creatine phosphokinase, myalgia, tremor
Respiratory: Cough, throat irritation
Miscellaneous: Fever
<1%, postmarketing, and/or case reports: Agranulocytosis, anemia, angioedema, atrial fibrillation, atrioventricular block (first and second degree), bradycardia, candidiasis, cholecystitis, decreased hemoglobin, decreased platelet count, dehydration, esophagitis, febrile neutropenia, flushing, hepatitis, herpes zoster, hyperbilirubinemia, hyperkalemia, increased blood urea nitrogen, increased C-reactive protein, increased troponin, intestinal obstruction, leukopenia, neutropenia, palpitations, pneumonia, pneumonitis, pneumothorax, prolonged QT-interval on ECG, pulmonary aspergillosis, renal insufficiency, respiratory failure, supraventricular tachycardia, ulcer with hemorrhage (gastric), ventricular tachycardia, viral respiratory tract infection, xanthoderma
Warnings/Precautions
Concerns related to adverse effects:
• CNS effects: May cause dizziness and/or fatigue which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Incidence of dizziness may be reduced by administering with food. Dose reduction or discontinuation may be necessary if symptoms fail to improve or worsen.
• GI effects: Adverse effects including nausea/vomiting, diarrhea, dyspepsia, gastroesophageal reflux disease, and abdominal pain have been reported; incidence may be reduced by administering with food. The incidence of gastrointestinal events was highest early in the course of treatment (initial 3 months) and decreased over time. Consider dose reduction or discontinuation of therapy if lack of improvement or worsening of symptoms.
• Hepatic effects: Increased transaminases (ALT/AST) and hyperbilirubinemia have been reported with use; evaluate liver function prior to therapy initiation and during therapy. Dose reduction or discontinuation of therapy may be necessary. Discontinue therapy immediately for transaminases >5 x ULN or for increased transaminases that are accompanied by symptoms (eg, jaundice) or hyperbilirubinemia; monitor closely and do not rechallenge with pirfenidone.
• Photosensitivity: Photosensitivity reactions and rash have been reported with the majority of reactions occurring during the initial 6 months of therapy (severe reactions are uncommon); instruct patients to avoid or minimize exposure to the sun and/or sun lamps, to apply sunscreen (SPF ≥50 against UVA and UVB), wear protective clothing/hats, and to avoid concurrent use of other photosensitizing drugs. Patients should promptly report symptoms, reaction, or rash; dose reduction or therapy interruption may be necessary. If appropriate, may reinitiate therapy with re-escalation of dose as tolerated.
• Weight loss: Weight loss/anorexia have been reported with use; monitor weight during therapy.
Disease-related concerns:
• Hepatic impairment: Use with caution in mild to moderate impairment (Child-Pugh class A and B); pirfenidone systemic exposure increased by 60% in moderate impairment. Use in severe impairment (Child-Pugh class C) is not recommended (has not been studied).
• Renal impairment: Use with caution in patients with renal impairment; consider dose reduction and/or discontinuation as necessary; use in patients with end stage renal disease requiring dialysis is not recommended.
Concurrent drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Special populations:
• Cigarette smokers: Clearance may be increased and systemic exposure decreased in cigarette smokers due to hepatic enzyme (ie, CYP1A2) induction. Patients should be instructed to quit smoking prior to initiation of therapy; cigarette smoking should be avoided during therapy.
Monitoring Parameters
Hepatic function (prior to initiation, monthly for first 6 months, then every 3 months); signs of photosensitivity; gastrointestinal events (eg, diarrhea, nausea, vomiting); weight loss
Pregnancy Considerations
Adverse events have been observed in animal reproduction studies.
Patient Education
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience dizziness, heartburn, common cold symptoms, joint pain, lack of appetite, change in taste, loss of strength and energy, insomnia, headache, or weight loss. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), angina, severe diarrhea, severe nausea, vomiting, severe abdominal pain, sunburn, bleeding, or bruising (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients
