Kaftrio 75 mg, 50 mg, 100 mg film coated tablets *

Pharmacy Only: Prescription

Addition of new presentation for the 6 to less than 12 years age group to the PIL.

1.What Kaftrio is and what it is used for

• Update to the indication statement for patients who are 6 years and older.

2. What you need to know before you take Kaftrio

• Update to header “Children under..” and safety and efficacy statement, that it is not known if Kaftrio is safe and effective in children under the age of 6 years

3. How to take Kaftrio

• Addition of statement that the doctor will determine the correct dose for the patient.
• Addition of dose recommendation table with information for the 6yrs and older age group added. The table also includes dosing information related to weight.
• Statement regarding Kaftrio usually being taken with ivacaftor has been moved so it is above the dose recommendation information/table.

 6. Contents of the pack and other information

• Minor formatting/header updates related to the new strength of Kaftrio with inclusion of composition and what the Kaftrio 37.5 mg/25 mg/50 mg film‑coated tablets look like.
• Clarification in the manufacturer’s address that Almac Craigavon is in Northern Ireland within the United Kingdom.

Minor typographical changes throughout the SmPC and table numbers updated.

1.            NAME OF THE MEDICINAL PRODUCT

Addition of new strength for the 6 to <12yrs age group Kaftrio 37.5mg/25mg/50mg film-coated tablets

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Addition of new strength with composition of Kaftrio given for ivacaftor 37.5mg, tezacaftor 25 mg and elexacaftor 50 mg.

Header added to differentiate both strengths.

3.         PHARMACEUTICAL FORM

Addition of description of tablets for 6 <12 yrs age group.

Header added to differentiate both strengths.

4.1       Therapeutic indications

Indication for Kaftrio in a combination regimen with ivacaftor updated to include patients who are 6 years and older.

4.2          Posology and method of administration

Dose recommendations table added. Information for the 6 to <12 years age group and weights ( <30kg and >30kg) have been included. The dosing information for patients 12 yrs and older is also included in the new table.

Statement below the table regarding the morning and evening dose has been updated to clarify that  both the morning and evening dose should be taken 12 hours apart with fat-containing food.

Statement regarding the safety and efficacy of Kaftrio in combination with ivacaftor has been updated from less than 12 yrs to less than 6 yrs given the indication update.

4.8          Undesirable effects

Clarification statement added above the adverse reactions table (Table 4) that with each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Addition of information related to study 445-106 ( 24-week open label study) in patients aged 6 to less than 12 years, stating that the safety data from this study was consistent with the pivotal study 445-102. In the paediatric populations subsection, data from the study for maximum transaminase (ALT or AST), transaminases elevations and total bilirubin have been clarified.

5.1      Pharmacodynamic properties

Pharmacodynamic effects subsection

Addition of sweat chloride data from study 445-106 for patients aged 6 to less than 12 years who are homozygous for F508del mutation or heterozygous for the F508del mutations and a minimal function mutation.

Clinical efficacy and safety

Addition of data from study 445-106 for the 6 to <12 years patient group including ppFEV₁ and table Table 8 for secondary efficacy outcomes (including ppFEV₁, CFQ-R Respiratory Domain score, BMI, Weight for age, Height for age, Number of pulmonary exacerbations and Lung Clearance Index).

5.2       Pharmacokinetic properties

Minor updates to Table 9 (Pharmacokinetic parameters). Addition of “SS” to clarify AUC parameter (area under curve) is at “steady state”.

Addition of definition of eGFR as estimated glomerular filtration rate.

Minor updates to age ranges in the paediatric population subsection, including addition of data to Table 10 related to mean elexacaftor (ELX), M23-ELX, tezacaftor(TEZ), M1-TEZ and ivacaftor ( IVA) exposures observed at steady state, by age group and dose administered.

8.         MARKETING AUTHORISATION NUMBER(S)

Addition of marketing authorisation number for new strength (6 to <12 years).

Summary of changes 

• Section 4 Possible side effects (Serious side effects-Possible signs of liver problems)

Summary of changes 

• Section 4.4 Special warnings and precautions for use (hepatic update)
• Changes to the references
• Section 4.8 Undesirable effects (Table 3 Adverse reactions and footnote)
• Section 4.8 Description of selected adverse reactions (Transaminase elevations)
• Correction to spelling and typing errors

Section 1: What Kaftrio is and what is it used for

Indication changed to: Kaftrio taken with ivacaftor is for patients aged 12 years and older who have CF, with at least one F508del mutation in the CFTR (cystic fibrosis transmembrane conductance regulator) gene.”

4.1 Therapeutic Indications

Updated indication to “Kaftrio is indicated in a combination regimen with ivacaftor 150 mg tablets for the treatment of cystic fibrosis (CF) in patients aged 12 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulatory (CFTR) gene.”

4.2 Posology and method of administration

Updated to match indication

Section 4.4 Special warnings and precautions for use: Elderly Population

Updated information to indicate studies did not include patients over 65 years old

Section 4.8: Undesirable effects: Summary of safety profile

Updated with study 445-104

Section 4.8: Undesirable effects: Paediatric population

Updated number of patients in safety data

5.1: Pharmacodynamic properties

Updated to include information on non-F508del CFTR variants

5.1: Pharmacodynamic properties- Effects on sweat chloride

Added Study 445-104 information and data

5.1: Pharmacodynamic properties- Clinical efficacy and safety

Added efficacy data for patients homozygous for F508del mutation or heterozygous for F508del mutation and a mutation with MF, a gating defect, or residual CFTR activity on the second allele

Study 445-104 added

Table 6: Primary and secondary efficacy analyses, full analysis set (study 445-104) added

Update to include local representative details for MAH holder in the PIL.

Initial Marketing Authorisation: 21 August 2020

Initial Marketing Authorisation: 21 August 2020