Pirfenidone is indicated for the treatment of adults with mild to moderate Idiopathic Pulmonary Fibrosis (IPF).

Pirfenidone is a novel therapeutic agent with anti-inflammatory, antioxidant, and anti-fibrotic effects. It helps improve lung function and may reduce the frequency of acute exacerbations in patients with idiopathic pulmonary fibrosis (IPF). The exact mechanism of action and molecular targets of pirfenidone are not fully understood. However, one of its key anti-fibrotic actions is the inhibition of transforming growth factor-β1 (TGF-β1), an important cytokine involved in fibrosis and extracellular matrix formation. Additionally, pirfenidone may reduce the expression of pro-inflammatory cytokines such as TNF-α, interleukin-1, and interferon-gamma. Studies in animal models have shown that pirfenidone can inhibit inflammatory cell infiltration and reduce increased pulmonary vascular permeability caused by bleomycin.

Route of administration: Pirfenidone is administered orally with food.

Adults: Upon initiating treatment, the dose should be titrated to the recommended daily dose of nine 267 mg tablets or three 801 mg tablet per day over a 14-days period as follows:

• Days 1 to 7: One 267 mg tablet administered three times a day (801 mg/day)
• Days 8 to 14: Two 267 mg tablets administered three times a day (1602 mg/day)
• Day 15 onward: Three 267 mg tablets or one 801 mg tablet administered three times a day (2403 mg/day)

The recommended daily dose of Pirfenidone for patients with IPF is three 267 mg tablets or one 801 mg three times a day with food for a total of 2403 mg/day. Doses above 2403 mg/day are not recommended for any patient. Patients who miss 14 consecutive days or more of Pirfenidone treatment should re-initiate therapy by undergoing the initial 2-week titration regimen up to the recommended daily dose. For treatment interruption of less than 14 consecutive days, the dose can be resumed at the previous recommended daily dose without titration.

Dose adjustments and other considerations for safe use: Gastrointestinal events: In patients who experience intolerance to therapy due to gastrointestinal side effects, patients should be reminded to take the medicinal product with food. If symptoms persist Pirfenidone may be reduced to 1-2 tablets (267 mg-534 mg) 2-3 times/day with food with re-escalation to the recommended daily dose as tolerated. If symptoms continue, patients may be instructed to interrupt treatment for 1 to 2 weeks to allow symptoms to resolve.

Photosensitivity reaction or rash: Patients who experience a mild to moderate photosensitivity reaction or rash should be reminded of the instruction to use a sunblock daily and to avoid sun exposure. The dose of Pirfenidone may be reduced to three 267 mg tablets/day (one 267 mg tablet three times a day). If the rash persists after 7 days, Pirfenidone should be discontinued for 15 days, with re-escalation to the recommended daily dose in the same manner as the dose escalation period. Patients who experience severe photosensitivity reaction or rash should be instructed to interrupt the dose and to seek medical advice. Once the rash has resolved, Pirfenidone may be re-introduced and re-escalated up to the recommended daily dose at the discretion of the physician.

Hepatic function: In the event of significant elevation of alanine and/or aspartate aminotransferases (ALT/AST) with or without bilirubin elevation, the dose of Pirfenidone should be adjusted or treatment discontinued according to the guidelines.

With medicines: Moderate (e.g., ciprofloxacin) and strong CYP1A2 inhibitors (e.g., fluvoxamine) can increase the systemic exposure of pirfenidone and may change its adverse effect profile. Fluvoxamine should be discontinued before starting pirfenidone or the dose of pirfenidone should be reduced to 267 mg three times daily. Dose reduction should also be considered when used with ciprofloxacin.

With food and others: No significant interactions reported. A lower incidence of adverse effects has been observed when pirfenidone is taken with food compared to fasting conditions.

Hypersensitivity to pirfenidone or any of its excipients, concomitant use with fluvoxamine, severe hepatic impairment or end-stage liver disease, severe renal impairment (CrCl <30 mL/min), or end-stage renal disease requiring dialysis.

Common: Nausea, rash, abdominal pain, upper respiratory tract infection, diarrhea, fatigue, headache, dyspepsia, dizziness, vomiting, anorexia, gastroesophageal reflux disease, sinusitis, insomnia, weight loss, and arthralgia.

Rare: Photosensitivity reactions, decreased appetite, pruritus, asthenia, dysgeusia, and non-cardiac chest pain.

Pregnancy: There are no adequate data on the use of pirfenidone in pregnant women. Animal studies have shown placental transfer of pirfenidone and/or its metabolites, with possible accumulation in amniotic fluid. At high doses, prolonged gestation and reduced fetal survival were observed in rats. As a precaution, use during pregnancy should be avoided.

Lactation: It is not known whether pirfenidone or its metabolites are excreted in human milk. Animal studies indicate that the drug and/or its metabolites are present in milk, with potential accumulation. A risk to the breastfed infant cannot be excluded. A decision should be made whether to discontinue breastfeeding or discontinue pirfenidone therapy, considering the benefits for both mother and child.

Fertility: Pirfenidone showed no adverse effects on fertility or reproductive performance in rats at doses up to 1000 mg/kg/day (approximately 3 times the maximum recommended human dose on a mg/m² basis).

• Elevated liver enzymes: Increases in ALT, AST, and bilirubin levels have been observed with pirfenidone use. Liver function tests should be monitored before and during therapy. Dose reduction or temporary discontinuation may be necessary.
• Photosensitivity and rash: Pirfenidone may cause photosensitivity reactions and skin rash. Patients should avoid direct sunlight and sunlamps, and use sunscreen along with protective clothing. Dose adjustment or temporary discontinuation may be required.
• Gastrointestinal disorders: Adverse effects such as nausea, vomiting, diarrhea, dyspepsia, gastroesophageal reflux disease, and abdominal pain may occur. Dose reduction or temporary discontinuation may be needed.

Children & Adolescents: The safety and effectiveness of pirfenidone in pediatric patients have not been established.

Hepatic Impairment: Patients should be monitored for adverse reactions, and dose modification or discontinuation should be considered if necessary. Pirfenidone is not recommended in severe hepatic impairment.

Renal Impairment: Monitor for adverse reactions and adjust or discontinue treatment as needed. Pirfenidone is not recommended in patients with end-stage renal disease requiring dialysis.

Smokers: Reduced drug exposure has been observed in smokers, which may affect the effectiveness of pirfenidone.

Clinical experience with overdose is limited. In studies, doses up to 4806 mg/day (given as six 267 mg tablets three times daily) were administered to healthy adults over 12 days. Reported adverse effects were mild, temporary, and consistent with known side effects of pirfenidone.

Immunosuppressant

Store in a cool and dry place. Protect from light and moisture. Keep out of reach of children.