PIRFENIDONE

Treatment with Pirfenidone Film-coated Tablets 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 Film-coated Tablets is 801 mg three times a day with food for a total of 2403 mg/day.

9). Patients who miss 14 consecutive days or more of Pirfenidone Film-coated Tablets 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 Film-coated Tablets 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 Film-coated Tablets 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%). UTabulated list of adverse reaction 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.

Table 1:

Adverse reactions by SOC and MedDRA frequency Infections and infestations Very Common Upper respiratory tract infection Common Urinary tract infection Blood and lymphatic system disorders Uncommon AgranulocytosisP1 Immune system disorders Uncommon AngioedemaP1 Not known AnaphylaxisP1 Metabolism and nutrition disorders Very Common Weight decreased; decreased appetite Uncommon Hyponatraemia1 Psychiatric disorders Very Common Insomnia Nervous system disorders Very Common Headache; dizziness Common Somnolence; dysgeusia; lethargy Vascular disorders Common Hot flush Respiratory, thoracic and mediastinal disorders Very Common Dyspnoea; cough Common Productive cough Gastrointestinal disorders Very Common Dyspepsia; nausea; diarrhoea; gastroesophageal reflux disease; vomiting; constipation Common Abdominal distension; abdominal discomfort; abdominal pain; abdominal pain upper; stomach discomfort; gastritis; flatulence Hepatobiliary disorders Common ALT increased; AST increased; gamma glutamyl transferase increased Uncommon Total serum bilirubin increased in combination with increases of ALT and ASTP1P; Drug-induced liver injuryP2 Skin and subcutaneous tissue disorders Very Common Rash Common Photosensitivity reaction; pruritus; erythema; dry skin; rash erythematous; rash macular; rash pruritic Not known Stevens-Johnson syndrome1; toxic epidermal necrolysis1; drug reaction with eosinophilia and systemic symptoms (DRESS)1 Musculoskeletal and connective tissue disorders Very Common Arthralgia Common Myalgia General disorders and administration site conditions Very Common Fatigue Common Asthenia; non-cardiac chest pain Injury poisoning and procedural complications Common Sunburn 1.

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 Film-coated Tablets treatment in this population.

2). Renal impairment No dose adjustment is necessary in patients with mild renal impairment. Pirfenidone Film-coated Tablets 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 Film-coated Tablets are for oral use. 2). 1. 5). 4). 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 Upper limit of normal (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 Film-coated Tablets should be reduced or interrupted. Once liver function tests are within normal limits Pirfenidone Film-coated Tablets 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.

1. 5). 4). 2)