Usage
Pirfenidone is prescribed for the treatment of idiopathic pulmonary fibrosis (IPF), a chronic and progressive lung disease characterized by scarring and stiffening of the lungs. It belongs to the pharmacological classification of antifibrotic agents. The precise mechanism of action remains incompletely understood, but it is believed to inhibit the production of transforming growth factor-beta (TGF-β) and other growth factors implicated in fibrosis. It also exhibits anti-inflammatory and antioxidant properties.
Alternate Names
The generic name is pirfenidone. A common brand name is Esbriet®.
How It Works
Pharmacodynamics: Pirfenidone reduces the production of TGF-β and other pro-fibrotic cytokines and growth factors. It also decreases fibroblast proliferation and collagen synthesis, thereby slowing down the progression of lung fibrosis. It demonstrates anti-inflammatory effects by downregulating inflammatory mediators like tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β). Additionally, it possesses antioxidant properties that may protect against oxidative stress in the lungs.
Pharmacokinetics: Pirfenidone is well absorbed orally, particularly when taken with food. It is primarily metabolized in the liver, mainly by CYP1A2, with minor contributions from other CYP enzymes like CYP2C9, 2C19, and 2D6. It is mostly eliminated through renal excretion. The half-life is approximately 2-3 hours.
Mode of Action: While not fully elucidated, the precise molecular mechanisms underlying pirfenidone’s antifibrotic effects involve modulation of various signaling pathways and cellular processes linked to fibrogenesis. It interferes with TGF-β signaling, reduces fibroblast proliferation and differentiation, and inhibits the synthesis of extracellular matrix components like collagen. These actions collectively lead to a reduction in the excessive accumulation of fibrous tissue in the lungs.
Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Pirfenidone is a substrate of CYP1A2, and its metabolism can be affected by strong or moderate CYP1A2 inhibitors or inducers.
Elimination Pathways: Primarily renal excretion, with hepatic metabolism via CYP1A2 playing a significant role.
Dosage
Standard Dosage
Adults:
Initial dose: 267 mg orally three times a day with food for 7 days.
Second week: 534 mg orally three times a day with food.
Maintenance dose (from Day 15 onward): 801 mg orally three times a day with food (maximum 2403 mg/day).
Children:
Safety and efficacy have not been established in pediatric patients. Use is not recommended.
Special Cases:
- Elderly Patients: No dose adjustment is typically necessary.
- Patients with Renal Impairment: Use with caution. Dose modification may be considered, especially in severe impairment. Not recommended in end-stage renal disease requiring dialysis.
- Patients with Hepatic Dysfunction: Use with caution in mild to moderate impairment (Child-Pugh A and B). Close monitoring and potential dose adjustments may be needed. Contraindicated in severe hepatic impairment (Child-Pugh C).
- Patients with Comorbid Conditions: Exercise caution in patients with other medical conditions, particularly those affecting liver or kidney function.
Clinical Use Cases
Pirfenidone is specifically indicated for IPF. It’s not typically used in clinical scenarios like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
Dose reductions may be necessary for patients experiencing significant gastrointestinal side effects, photosensitivity reactions, or rash. Concomitant use of strong CYP1A2 inhibitors necessitates dose reductions. Liver enzyme elevations may require dose adjustments or discontinuation.
Side Effects
Common Side Effects
Nausea, vomiting, diarrhea, heartburn, stomach pain, headache, dizziness, upper respiratory tract infections, fatigue, loss of appetite, sinusitis, insomnia, weight loss, rash, photosensitivity.
Rare but Serious Side Effects
Liver problems (jaundice, dark urine, abdominal pain), severe skin reactions (blisters, rash, sores), angioedema (swelling of face, lips, tongue), severe photosensitivity.
Long-Term Effects
The most significant long-term effect is the potential for liver damage with prolonged use. Regular monitoring of liver function is crucial.
Adverse Drug Reactions (ADR)
Angioedema, severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), hepatotoxicity.
Contraindications
Hypersensitivity to pirfenidone, history of angioedema with pirfenidone, concomitant use of fluvoxamine, severe hepatic impairment, severe renal impairment requiring dialysis.
Drug Interactions
Fluvoxamine (strong CYP1A2 inhibitor – contraindicated), ciprofloxacin (moderate CYP1A2 inhibitor – dose reduction required), strong CYP1A2 inducers (e.g., rifampin, carbamazepine, phenobarbital – reduce pirfenidone effectiveness), smoking (decreases pirfenidone levels), grapefruit juice (inhibits CYP1A2 – avoid).
Pregnancy and Breastfeeding
Pregnancy Safety Category: B3 (Australia); Not assigned (US). Use should generally be avoided during pregnancy and breastfeeding due to limited data on human safety. Animal studies suggest potential for fetal harm at high doses.
Drug Profile Summary
- Mechanism of Action: Antifibrotic, anti-inflammatory, and antioxidant. Inhibits TGF-β and other growth factors, reduces fibroblast proliferation and collagen synthesis.
- Side Effects: Nausea, rash, photosensitivity, gastrointestinal issues, fatigue, headache. Rarely: liver problems, severe skin reactions, angioedema.
- Contraindications: Hypersensitivity, angioedema history with pirfenidone, fluvoxamine use, severe hepatic or renal impairment.
- Drug Interactions: Fluvoxamine, ciprofloxacin, CYP1A2 inducers, smoking, grapefruit juice.
- Pregnancy & Breastfeeding: Avoid due to limited safety data.
- Dosage: Titrate up to 801 mg TID with food. Max 2403 mg/day. Adjustments for renal/hepatic impairment.
- Monitoring Parameters: Liver function tests, weight, skin reactions, signs of angioedema.
Popular Combinations
No specific drug combinations are routinely recommended with pirfenidone for synergistic effects in IPF. Treatment decisions are individualized based on patient needs and potential drug interactions.
Precautions
- General Precautions: Assess liver and kidney function before starting and monitor regularly. Screen for allergies.
- Specific Populations: Avoid in pregnancy/breastfeeding. Use with caution in elderly and those with renal/hepatic impairment.
- Lifestyle Considerations: Avoid smoking, grapefruit juice, excessive sun exposure.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Pirfenidone?
A: Adults: Start at 267 mg TID with food, titrate up to 801 mg TID with food over 14 days. Max 2403 mg/day. Pediatric: Not recommended. Dose adjustments needed for renal/hepatic impairment.
Q2: What is the mechanism of action of Pirfenidone?
A: It’s an antifibrotic, anti-inflammatory, and antioxidant agent. It inhibits TGF-β and other growth factors involved in fibrosis.
Q3: What are the most common side effects of Pirfenidone?
A: Nausea, rash, photosensitivity, gastrointestinal issues, fatigue, headache.
Q4: What are the serious side effects of Pirfenidone?
A: Liver damage, severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), angioedema.
Q5: What are the contraindications for Pirfenidone?
A: Hypersensitivity, history of angioedema with pirfenidone, fluvoxamine use, severe liver or kidney disease.
Q6: What are the key drug interactions with Pirfenidone?
A: Fluvoxamine (contraindicated), ciprofloxacin (dose adjustment required), strong CYP1A2 inducers, smoking, grapefruit juice.
Q7: Can Pirfenidone be used in pregnancy or breastfeeding?
A: It should be avoided due to potential fetal harm. Discuss risks and benefits with the patient if necessary.
Q8: How should liver function be monitored in patients taking Pirfenidone?
A: Liver function tests (LFTs) should be performed before treatment initiation and periodically thereafter, with increased frequency during the first six months.
Q9: What patient education is crucial for Pirfenidone?
A: Emphasize taking the medication with food, sun protection, and reporting any signs of liver problems or skin reactions. Advise on potential drug and lifestyle interactions.
Q10: What should be done if a patient develops a rash while taking Pirfenidone?
A: Evaluate the severity of the rash. For mild to moderate rashes, advise sun protection and consider dose reduction. Discontinue if severe or persistent.
