M-PIRFENIDONE

and 9 DRUG INTERACTIONS). Strong and Selective Inhibitors of CYP1A2 In vitro-in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 have the potential to increase the exposure to pirfenidone by approximately 2 to 4-fold.

If concomitant use of M-PIRFENIDONE with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of M-PIRFENIDONE should be reduced to 801 mg daily (267 mg, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with M-PIRFENIDONE therapy.

Discontinue M-PIRFENIDONE if necessary (see 4 DOSAGE AND ADMINISTRATION and 9 DRUG INTERACTIONS). , CYP2C9, 2C19, 2D6, and 2E1) should be avoided during M-PIRFENIDONE treatment. M- PIRFENIDONE should be used with caution in patients treated with moderate inhibitors of CYP1A2 that do not inhibit other CYP isoenzymes (see 9 DRUG INTERACTIONS).

1 Dosing Considerations • Treatment with M-PIRFENIDONE should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of IPF. • M-PIRFENIDONE should be taken with food (see 9 DRUG INTERACTIONS).

• M-PIRFENIDONE should not be taken concomitantly with fluvoxamine (see 2 CONTRAINDICATIONS, 7 WARNINGS AND PRECAUTIONS and 9 DRUG INTERACTIONS). • Reduction of the M-PIRFENIDONE dose may be required for ciprofloxacin and strong but selective inhibitors of CYP1A2 (see 7 WARNINGS AND PRECAUTIONS and 9 DRUG INTERACTIONS).

2 Recommended Dose and Dosage Adjustment Adults The recommended daily dose of M-PIRFENIDONE for patients with IPF is 801 mg three times a day with food, for a total dose of 2403 mg/day. Upon initiating treatment, the dose should be titrated to the recommended daily dose of 2403 mg/ day over a 14-day period to improve tolerability as follows: Days 1 to 7: a dose of 267 mg administered, three times a day (801 mg/day) with food.

Days 8 to 14: a dose of 534 mg administered, three times a day (1602 mg/day) with food. Day 15 onward: a dose of 801 mg administered, three times a day (2403 mg/day) with food. M-PIRFENIDONE (Pirfenidone Tablets) Page 6 of 43 Doses above 2403 mg/day are not recommended for any patient (see

, Post-Market Adverse Reactions). Liver chemistry tests (ALT, AST, and bilirubin) should be performed prior to the initiation of treatment with M- PIRFENIDONE, and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter.

In addition, liver function tests should be promptly measured in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. In the event of elevations of ALT and/or AST, or clinical signs and symptoms of liver injury, the dose of M-PIRFENIDONE may need to be reduced or treatment discontinued (see 7 WARNINGSAND PRECAUTIONS, Monitoring and Laboratory Tests and 4 DOSAGE AND ADMINISTRATION, Recommendations in Case of ALT, AST, Bilirubin Elevations).

, Child-Pugh Class B), pirfenidone exposure was increased by 60%. , Child-Pugh Class A and B) given the potential for increased M-PIRFENIDONE exposure. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor (see

). • Concomitant use of fluvoxamine (see 7 WARNINGS AND PRECAUTIONS and 9 DRUG INTERACTIONS). • Severe hepatic impairment or end-stage liver disease (see 7 WARNINGS AND PRECAUTIONS). • Severe renal impairment (CrCl <30 mL/min) or end stage renal disease requiring dialysis (see 7 WARNINGS AND PRECAUTIONS).

3 SERIOUS WARNINGS AND PRECAUTIONS BOX Drug Interactions with Inhibitors of CYP1A2 and Other CYP Isoenzymes Fluvoxamine M-PIRFENIDONE is contraindicated in patients with concomitant use of fluvoxamine (a strong inhibitor of CYP1A2 with inhibitory effects on CYP2C9, 2C19, and 2D6).

Fluvoxamine should be discontinued prior to the initiation of treatment with M-PIRFENIDONE and avoided during M-PIRFENIDONE therapy due to the potential for reduced clearance of pirfenidone (see 2 CONTRAINDICATIONS and 9 DRUG INTERACTIONS).

Ciprofloxacin Co-administration of pirfenidone and 750 mg of ciprofloxacin (a moderate and selective inhibitor of CYP1A2) increased the exposure to pirfenidone by 81%. If ciprofloxacin at the dose of 750 mg twice daily (a total daily dose of 1500 mg) cannot be avoided, the dose of M-PIRFENIDONE should be reduced to 1602 mg daily (a dose of 534 mg, three times a M-PIRFENIDONE (Pirfenidone Tablets) Page 5 of 43 day).

M-PIRFENIDONE should be used with caution when ciprofloxacin is used at a total daily dose of 250 to 1000 mg (see 4 DOSAGE AND ADMINISTRATION and 9 DRUG INTERACTIONS). Strong and Selective Inhibitors of CYP1A2 In vitro-in vivo extrapolations indicate that strong and selective inhibitors of CYP1A2 have the potential to increase the exposure to pirfenidone by approximately 2 to 4-fold.

If concomitant use of M-PIRFENIDONE with a strong and selective inhibitor of CYP1A2 cannot be avoided, the dose of M-PIRFENIDONE should be reduced to 801 mg daily (267 mg, three times a day). Patients should be closely monitored for emergence of adverse reactions associated with M-PIRFENIDONE therapy.

• Hypersensitivity to this drug or to any ingredient in the formulation, including any non- medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING section of the product monograph.

• History of angioedema with pirfenidone (see 7 WARNINGS AND PRECAUTIONS). • Concomitant use of fluvoxamine (see 7 WARNINGS AND PRECAUTIONS and 9 DRUG INTERACTIONS). • Severe hepatic impairment or end-stage liver disease (see 7 WARNINGS AND PRECAUTIONS).

• Severe renal impairment (CrCl <30 mL/min) or end stage renal disease requiring dialysis (see 7 WARNINGS AND PRECAUTIONS).