ORKAMBI

1 Dosing Considerations ORKAMBI should only be administered to patients who have a mutation in the CFTR gene listed in 1 INDICATIONS. ORKAMBI should only be prescribed by healthcare professional with experience in the treatment of cystic fibrosis.

If the patient’s genotype is unknown, an accurate and validated genotyping method should be performed to confirm the presence of the F508del mutation on both alleles of the CFTR gene. 2 Recommended Dose and Dosage Adjustment Adults, Adolescents, and children aged 1 year and older The recommended daily dose of ORKAMBI in adult and pediatric patients aged 1 year and older PrORKAMBI® (Lumacaftor/Ivacaftor Tablets and Granules) Page 5 of 47 Unclassified / Non classifié is based on patient’s age and weight as detailed in Table 1.

3 Pharmacokinetics). ORKAMBI granules and tablets should be taken with fat-containing food. 4 Administration). Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A dose reduction is recommended for patients with moderate hepatic impairment (Child-Pugh Class B).

Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, after weighing the risks and benefits of treatment, ORKAMBI should be used with caution, at a reduced dose, in patients with severe hepatic impairment (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests, 8 ADVERSE REACTIONS, and 10 CLINICAL PHARMACOLOGY).

For dose adjustments for patients with hepatic impairment refer to Table 2.

Table 2:

Dosage Adjustment Recommendations for Patients with Hepatic Impairment Hepatic Insufficiency Age Dose Adjustment* Morning Dose Evening Dose Mild hepatic impairment (Child-Pugh Class A) 1 to 5 years No dose adjustment 1 packet No dose adjustment 1 packet 6 years and older No dose adjustment 2 tablets No dose adjustment 2 tablets Moderate hepatic impairment (Child-Pugh 1 to 5 years Day 1: 1 packet Day 2: 1 packet Day 1: 1 packet Day 2: Skip evening dose PrORKAMBI® (Lumacaftor/Ivacaftor Tablets and Granules) Page 6 of 47 Unclassified / Non classifié Table 2: Dosage Adjustment Recommendations for Patients with Hepatic Impairment Hepatic Insufficiency Age Dose Adjustment* Morning Dose Evening Dose Class B) 6 years and older 2 tablets 1 tablet Severe hepatic impairment (Child-Pugh Class C) 1 to 5 years 1 packet of granules per day** 6 years and older 1 tablet 1 tablet *See Table 1 for the appropriate dose per unit based on age and weight.

, and 10 CLINICAL PHARMACOLOGY). For dose adjustments for patients with hepatic impairment refer to Table 2.

Table 2:

Dosage Adjustment Recommendations for Patients with Hepatic Impairment Hepatic Insufficiency Age Dose Adjustment* Morning Dose Evening Dose Mild hepatic impairment (Child-Pugh Class A) 1 to 5 years No dose adjustment 1 packet No dose adjustment 1 packet 6 years and older No dose adjustment 2 tablets No dose adjustment 2 tablets Moderate hepatic impairment (Child-Pugh 1 to 5 years Day 1: 1 packet Day 2: 1 packet Day 1: 1 packet Day 2: Skip evening dose PrORKAMBI® (Lumacaftor/Ivacaftor Tablets and Granules) Page 6 of 47 Unclassified / Non classifié Table 2: Dosage Adjustment Recommendations for Patients with Hepatic Impairment Hepatic Insufficiency Age Dose Adjustment* Morning Dose Evening Dose Class B) 6 years and older 2 tablets 1 tablet Severe hepatic impairment (Child-Pugh Class C) 1 to 5 years 1 packet of granules per day** 6 years and older 1 tablet 1 tablet *See Table 1 for the appropriate dose per unit based on age and weight.

** or less frequently Elevated Liver Function Tests Dosing should be interrupted, and laboratory tests closely followed in patients with ALT or AST greater than 5 x upper limit of normal (ULN) when not associated with elevated bilirubin.

Dosing should also be interrupted, and laboratory tests closely followed in patients with ALT or AST elevations greater than 3 x ULN when associated with bilirubin elevations greater than 2 x ULN. Renal Impairment No dose adjustment is necessary for patients with mild to moderate renal impairment.

Caution is recommended while using ORKAMBI in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or end-stage renal disease (see 7 WARNINGS AND PRECAUTIONS and 10 CLINICAL PHARMACOLOGY). Concomitant CYP3A Inhibitors No dose adjustment is necessary when CYP3A inhibitors are initiated in patients currently taking ORKAMBI.

, Monitoring and Laboratory Tests,

ORKAMBI is contraindicated in patients who are hypersensitive 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.