Pirfenidone is a medication primarily used for the treatment of idiopathic pulmonary fibrosis (IPF), a progressive lung disease characterized by scarring of the lung tissue. Pirfenidone works by reducing fibrosis or the formation of scar tissue in the lungs. It is believed to have anti-inflammatory and anti-fibrotic properties.

Pirfenidone was approved for the treatment of IPF in several countries, including the United States, Europe, and Japan. It has been shown to slow the decline in lung function and improve progression-free survival in patients with IPF. However, it is important to note that pirfenidone does not cure IPF, but rather helps to slow its progression and improve symptoms.

Pirfenidone and nintedanib are the two currently FDA-approved drugs for the treatment of IPF (Idiopathic pulmonary fibrosis). Pirfenidone is an orally available antifibrotic drug that has been evaluated in multiple clinical trials. It is used to inhibit fibrosis in multiple conditions, including lung and liver fibrosis.

Pirfenidone Indications:

Pirfenidone in idiopathic pulmonary fibrosis:

Taniguchi et al studied pirfenidone in more than 200 Japanese patients with idiopathic pulmonary fibrosis. The study concluded that pirfenidone was well tolerated and effective in reducing the decline in the vital capacity and progression-free survival after 52 weeks. In the CAPACITY trial, the investigators found that pirfenidone was effective at weeks 24 and 48 in reducing the decline in vital capacity with the favorable benefit-risk profile. Another study " A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis" enrolled more than 500 patients with IPF. The investigators concluded that Pirfenidone reduced disease-free progression compared to placebo. It also resulted in a reduction in the decline of FVC (functional vital capacity) and improvement in the 6-minute walking distance. Pirfenidone is also studied in animals with bleomycin-induced fibrosis and has been found beneficial in these cases.

Pirfenidone and nintedanib in IPF:

In October 2014, two drugs became available in the United States for patients with IPF when the Food and Drug Administration (FDA) approved pirfenidone (Esbriet, InterMune) and nintedanib (Ofev, Boehringer Ingelheim). Pirfenidone is an antiinflammatory and antifibrotic drug while nintedanib is a tyrosine kinase inhibitor. Nintedanib and pirfenidone both have resulted in a reduction in the decline in FVC, however, nintedanib also protects against acute exacerbations and mortality in IPF. Pirfenidone and nintedanib have been given in combination as well. Studies have not resulted in an increase in adverse outcomes. Nintedanib did not affect pirfenidone levels, however, the nintedanib levels were lower when given in combination. When given in combination in patients with IPF, the results are slightly better than when each drug is given as monotherapy.

Pirfenidone in ILD (Interstitial lung disease) associated with systemic sclerosis:

A case series of five patients with scleroderma-associated interstitial lung disease has been published. All patients treated with pirfenidone resulted in an improvement in the vital capacity. Another patient with progressive pulmonary fibrosis associated with scleroderma was given pirfenidone 200 mg three times a day (a lower dose compared to that published in the major clinical trials) showed a reversal in lung function deterioration.

Pirfenidone in diabetic nephropathy:

It has also been studied in patients with diabetic nephropathy. Sharma et al studied the drug in 77 patients and did not find any improvement in the eGFR. However, in the placebo arm, 4 patients initiated hemodialysis, 1 patient initiated hemodialysis in the pirfenidone group receiving 2400 mg/day, and none in the pirfenidone group who received 1200 mg/day. Authors of another study " Pirefenidone is renoprotective in diabetic kidney disease" concluded, "PFD is renoprotective in diabetic kidney disease". The anti-fibrotic effects may in part be secondary to its effects on inhibiting RNA processing. It has also been found to reduce interstitial fibrosis and improves the decline in renal functions in animal models.

Pirfenidone in the liver and cardiac fibrosis:

Studies conducted on animals have resulted in a 50% reduction in liver fibrosis. Similarly, it has been found useful in experimental animal studies that had sclerosing peritonitis. Pirfenidone and spironolactone have been studied in diabetic kidney disease and diabetic cardiomyopathy in animal models. The authors conclude that the two drugs reverse fibrosis and improve the impairment in the functional status associated with the increased collagen deposition in these conditions.

Pirfenidone (Esbriet) dose in adults

Pirfenidone (Esbriet) dosage in the treatment of Idiopathic pulmonary fibrosis (IPF):

For pirfenidone in the treatment of idiopathic pulmonary fibrosis (IPF) when taken orally:

• Days 1 to 7: Take 267 milligrams three times a day (totaling 801 milligrams per day).
• Days 8 to 14: Increase to 534 milligrams three times a day (totaling 1,602 milligrams per day).
• Day 15 and afterward: Take 801 milligrams three times a day (totaling 2,403 milligrams per day). This is the maximum dose.

Reinitiation after interruption:

• If you miss taking it for less than 14 days, start again with the last dose you were taking.
• If it's more than 14 days, start over with the initial two-week dose increase period.

Dosage adjustment for other medications:

• If you're taking strong CYP1A2 inhibitors (like fluvoxamine), reduce pirfenidone to 801 milligrams total per day.
• If it's a moderate CYP1A2 inhibitor (like ciprofloxacin), reduce to 1,602 milligrams total per day when taking with ciprofloxacin at 1,500 milligrams per day.

Pirfenidone 200 mg:

A lower dose i.e. 200 mg three times a day has been found useful in interstitial lung disease associated with scleroderma.

Pirfenidone (Esbriet) dose in Childrens

It is not recommended for use in children.

Pregnancy Risk Category C

• In animal studies, some negative effects on reproduction have been noticed.

Use during breastfeeding:

• It's uncertain whether pirfenidone passes into breast milk.
• The manufacturer advises considering the potential risks of exposing the infant to the medication, the advantages of breastfeeding for the baby, and the benefits of the treatment for the mother when deciding whether to continue or stop breastfeeding during therapy.

Pirfenidone dosage in kidney disease:

• For individuals with mild to severe impairment, the manufacturer's instructions don't specify any dosage adjustments. However, it's advised to use the medication cautiously and consider modifying the dose or stopping it if necessary.
• For those with end-stage renal disease (ESRD) needing dialysis, using pirfenidone isn't recommended as it hasn't been studied in this population.

Pirfenidone dose in liver disease:

Hepatic Impairment Prior to Treatment Initiation:

• Mild to Moderate Impairment (Child-Pugh Class A and B): No dosage adjustments are provided. Use carefully; consider modifying the dose or stopping if necessary.
• Severe Impairment (Child-Pugh Class C): Not recommended to use as it hasn't been studied in this condition.

Hepatotoxicity During Treatment:

• ALT/AST >3 to ≤5 × ULN (without hyperbilirubinemia): Investigate other potential causes and stop medications that might cause confusion. Depending on clinical judgment, you may continue the current dose, reduce it (specific reductions not provided), or temporarily stop treatment. Once liver enzyme levels return to normal, you can gradually go back to the recommended dose. Keep a close eye on liver function tests (LFTs) afterward.
• ALT/AST >3 to ≤5 × ULN with hyperbilirubinemia or symptoms: Stop therapy immediately and do not restart.
• ALT/AST >5 × ULN (irrespective of bilirubin levels): Cease therapy immediately and refrain from restarting it.

Side Effects of Pirfenidone (Common side effects):

• Central Nervous System:
  • Fatigue
  • Headache
  • Dizziness
• Dermatologic:
  • Skin Rash
  • Skin Photosensitivity
• Gastrointestinal:
  • Nausea
  • Diarrhea
  • Abdominal Pain
  • Dyspepsia
  • Anorexia
  • Vomiting
  • Gastroesophageal Reflux Disease
• Respiratory:
  • Upper Respiratory Tract Infection
  • Sinusitis

Pirfenidone Side Effects (Less Common): 

• Central Nervous System:
  • Insomnia
  • Noncardiac Chest Pain
  • Drowsiness
• Dermatologic:
  • Pruritus
  • Macular Eruption
  • Sunburn
  • Erythema
• Endocrine & Metabolic:
  • Weight Loss
  • Increased Gamma-Glutamyl Transferase
  • Hot Flash
• Gastrointestinal:
  • Abdominal Distension
  • Decreased Appetite
  • Abdominal Distress
  • Dysgeusia
  • Flatulence
• Hepatic:
  • Increased Serum ALT
  • Increased Serum Transaminases
• Neuromuscular & Skeletal:
  • Arthralgia
  • Weakness
• Respiratory:
  • Dyspnea

Pirfenidone Side Effects (Uncommon): 

• 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

Contraindication to Pirfenidone Include:

Manufacturer's Labeling:

• Contraindications: There are no contraindications listed in the manufacturer's labeling.

Canadian Labeling (Additional Contradictions):

• Hypersensitivity: Avoid if allergic to pirfenidone or any ingredients in the formulation.
• History of Angioedema: Avoid if you've experienced angioedema (rapid swelling) with pirfenidone before.
• Concomitant Use of Fluvoxamine: Don't use pirfenidone alongside fluvoxamine.
• Severe Hepatic Impairment or End-Stage Liver Disease: Avoid if you have severe liver problems.
• Severe Renal Impairment or End-Stage Renal Disease: Don't use if you have severe kidney impairment (creatinine clearance less than 30 mL/minute) or need dialysis for end-stage renal disease.

Warnings and precautions

Neurological effects

• Pirfenidone may cause dizziness and fatigue, which can affect physical and mental abilities.
• Patients should be warned about tasks requiring alertness like driving or operating machinery.
• Taking pirfenidone with food may reduce the incidence of dizziness.
• If symptoms persist or worsen, dose reduction or discontinuation may be necessary.

GI effects

• Common adverse effects include nausea, vomiting, diarrhea, dyspepsia, and abdominal pain.
• Taking pirfenidone with food may decrease these symptoms.
• GI side effects are usually highest during the initial 3 months of treatment and decrease over time.
• Consider reducing the dose or stopping treatment if symptoms don't improve.

Hepatic effects

• Serious liver problems, including fatal cases, have been reported.
• Liver enzyme elevations can be reversed by adjusting or stopping the dose.
• Liver function tests (ALT, AST, bilirubin) should be done before starting treatment, monthly for the first 6 months, then every 3 months and as needed.
• Adjusting the dose or interrupting treatment may be necessary for elevated liver enzymes.

Photosensitivity

• Pirfenidone can cause photosensitivity reactions and rashes, especially in the first 6 months of therapy.
• Patients should avoid sunlight and use sunscreen (SPF ≥50) and protective clothing.
• Promptly report any symptoms, reactions, or rashes. Dose reduction or interruption may be needed.

Weight loss:

• Weight loss and decreased appetite are possible side effects. Weight should be monitored during treatment.

Hepatic impairment

• Use cautiously in mild to moderate liver impairment (Child-Pugh class A and B).
• Exposure to pirfenidone increases by 60% in moderate impairment.
• Not recommended for severe liver impairment (Child-Pugh class C) due to lack of studies.

Renal impairment

• Use with caution in patients with kidney problems. Consider dose reduction or discontinuation if needed.
• Not recommended for patients with end-stage renal disease requiring dialysis due to lack of studies.

Pirfenidone: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Risk Factor C (Monitor therapy)
Abiraterone Acetate	May increase the serum concentration of CYP1A2 Substrates (High risk with Inhibitors).
Aminolevulinic Acid (Topical)	Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical).
Broccoli	May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers).
Cannabis	May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers).
CYP1A2 Inducers (Moderate)	May decrease the serum concentration of Pirfenidone.
Cyproterone	May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers).
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.
Obeticholic Acid	May increase the serum concentration of CYP1A2 Substrates (High risk with Inhibitors).
Peginterferon Alfa-2b	May increase the serum concentration of CYP1A2 Substrates (High risk with Inhibitors).
Porfimer	Photosensitizing Agents may enhance the photosensitizing effect of Porfimer.
Teriflunomide	May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers).
Verteporfin	Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin.
Risk Factor D (Consider therapy modification)
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.
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).
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.
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. Drugs listed as exceptions to this monograph are discussed in separate drug interaction monographs.
Risk Factor X (Avoid combination)
Aminolevulinic Acid (Systemic)	Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic).
Tobacco (Smoked)	May decrease the serum concentration of Pirfenidone.

Monitor:

• Hepatic Function:
  • Before starting treatment.
  • Monthly for the first 6 months.
  • Every 3 months thereafter.
  • As clinically indicated.
• Signs of Photosensitivity:
  • Patients should be vigilant for any signs of photosensitivity reactions such as rash or skin irritation.
• Gastrointestinal Events:
  • Look out for symptoms like diarrhea, nausea, and vomiting, especially during the initial stages of treatment.
• Weight Loss:
  • Monitor weight regularly to detect any significant changes during the course of treatment.

How to administer Pirfenidone (Esbriet)?

• Pirfenidone should be taken orally with food at the same time each day.

Pirfenidone Mechanism of action:

• While the exact mechanisms of action are not completely understood, pirfenidone likely exhibits antifibrotic effects by reducing fibroblast proliferation and the production of proteins and cytokines associated with fibrosis.
• It may also decrease the formation and buildup of extracellular matrix, particularly collagen, in response to certain growth factors like transforming growth factor-beta and platelet-derived growth factor.
• Additionally, pirfenidone is thought to have anti-inflammatory properties by reducing the accumulation of inflammatory cells triggered by various stimuli.

Distribution:

• Approximately 59 to 71 liters in the body.

Protein Binding:

• On average, around 58%, primarily to albumin.

Metabolism:

• Mostly occurs in the liver, primarily by the enzyme CYP1A2, and to a lesser extent by CYP2C9, 2C19, 2D6, and 2E1.
• Its main metabolite, 5-carboxy-pirfenidone, is inactive.

Half-Life:

• The elimination half-life is approximately 3 hours.

Time to Peak Plasma Concentration:

• About 0.5 hours under fasting conditions and 3 hours when taken with food.

Excretion:

• Mostly excreted in the urine, with approximately 80% of the dose eliminated this way.
• More than 99% of the excreted material is in the form of metabolites.

Pirfenidone brand names (International):

• Esbriet
• Fibridoner
• Kitoscell
• Kitoscell LP
• Pirespa
• Pirfenex
• Pirfetab

Pirfenidone availability in Pakistan:

It is currently not registered in Pakistan but available in the markets by the brand name of Pirfenox 200 mg.