Pirfenidone Axunio (Previously Pirfenidone AET)

Treatment with Pirfenidone axunio should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of IPF. Posology Adults Upon initiating treatment, the dose should be titrated to the recommended daily dose of 2403 mg/day over a 14-day period as follows: • Days 1 to 7: a dose of 267 mg administered three times a day (801 mg/day) • Days 8 to 14: a dose of 534 mg administered three times a day (1602 mg/day) • Day 15 onward: a dose of 801 mg administered three times a day (2403 mg/day) The recommended maintenance daily dose of Pirfenidone axunio is 801 mg three times a day with food for a total of 2403 mg/day.

9). 3 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 undesirable effects, patients should be reminded to take the medicinal product with food.

If symptoms persist, the dose of pirfenidone may be reduced to 267 mg – 534 mg, two to three times a day with food with re-escalation to the recommended daily dose as tolerated. If symptoms continue, patients may be instructed to interrupt treatment for one to two weeks to allow symptoms to resolve.

4). The dose of pirfenidone may be reduced to 801 mg each day (267 mg 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.

4). 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 listed in section

1%). Tabulated list of adverse reactions The safety of pirfenidone has been evaluated in clinical studies including 1,650 volunteers and patients. More than 170 patients have been investigated in open studies for more than five years and some for up to 10 years.

Table 1 shows the adverse reactions reported at a frequency of ≥2% in 623 patients receiving pirfenidone at the recommended dose of 2,403 mg/day in three pooled pivotal Phase 3 studies. Adverse reactions from post-marketing experience are also listed in Table 1.

Adverse reactions are listed by System Organ Class (SOC) and within each frequency grouping [Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), not known (cannot be estimated from the available data)] the adverse reactions are presented in order of decreasing seriousness.

4). Exposure-adjusted analyses of pooled clinical trials in IPF confirmed that the safety and tolerability profile of pirfenidone in IPF patients with advanced disease (n=366) is consistent with that established in IPF patients with non-advanced disease (n=942).

Description of selected adverse reactions Decreased appetite During the pivotal clinical trials, cases of decreased appetite were readily manageable and generally not associated with significant sequelae. Uncommonly, cases of decreased appetite were associated with significant weight loss and required medical intervention.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4. 2). e. Child-Pugh Class A and B). However, since plasma levels of pirfenidone may be increased in some individuals with mild to moderate hepatic impairment, caution should be used with pirfenidone treatment in this population. 2). Renal impairment No dose adjustment is necessary in patients with mild renal impairment.

Pirfenidone should be used with caution in patients with moderate (CrCl 30-50 ml/min) renal impairment. 2). Paediatric population There is no relevant use of pirfenidone in the paediatric population for the indication of IPF. Method of administration Pirfenidone axunio is for oral use.

2). 1. 4). 5). 4). 2). 4 Special warnings and precautions for use Hepatic function Elevated transaminases have been commonly reported in patients treated with pirfenidone. 8). If a patient exhibits an aminotransferase elevation >3 to <5 x ULN without bilirubin elevation and without symptoms or signs of drug-induced liver injury after starting pirfenidone therapy, other causes should be excluded, and the patient monitored closely.

Discontinuation of other medicines associated with liver toxicity should be considered. If clinically appropriate, the dose of pirfenidone should be reduced or interrupted. Once liver function tests are within normal limits pirfenidone may be re- escalated to the recommended daily dose if tolerated.

Drug-induced liver injury Uncommonly, elevations in AST and ALT were associated with concomitant bilirubin increases. 8). In addition to the recommended regular monitoring of liver function tests, prompt clinical evaluation and measurement of liver function tests should be performed in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.

If a patient exhibits an aminotransferase elevation >3 to <5 x ULN accompanied by hyperbilirubinaemia or clinical signs or symptoms indicative of liver injury, pirfenidone should be permanently discontinued and the patient should not be rechallenged.

1. 4). 5). 4). 2).