• Addition of Depression section in 4.4
• Revision to breast-feeding text in 4.6
• Addition of Depression in Table 4: Adverse reactions in 4.8
• Updated revision date in 10

Millmount Healthcare Limited

Block-7, City North Business Campus

Stamullen

Co. Meath

K32 YD60

Ireland

This leaflet was last revised in October 2022.

Minor typographical changes and text updates throughout the PI.

Update to revise the word “medicine/s” with “medicinal product/s” throughout the PI.

Section 5: Pharmacological Properties

5.1 Pharmacodynamics Properties

Mechanism of action - Update to specify the reference to study 5 to include safety.

Section 9:

Date of latest renewal: 29 April 2022.

Section 10:

Date of revision of the text: 04/2022.

Section 5.1 Pharmacodynamic Properties - Paediatric population

Statement was added explaining that patients were eligible to enter an open-label, rollover, 96-week study.

Minor typographical changes throughout the PI and table numbers updated.

4.1       Therapeutic indications

Indication for ivacaftor/tezacaftor/elexacaftor 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 updated. Information for the 6 to <12 years age group and weights ( <30kg and >30kg) have been included for patients using ivacaftor in combination with ivacaftor/tezacaftor/elexacaftor.

Dose recommendations table for concomitant use with moderate or strong CYP3A inhibitors updated for the 6 to less than 12 years age group.

Dose recommendations table for moderate or strong severe hepatic impairment updated for the 6 to less than 12 years age group.

In paediatric population subsection the statement regarding the safety and efficacy of Kalydeco in combination with ivacaftor/tezacaftor/elexacaftor has been updated from less than 12 yrs to less than 6 yrs given the indication update.

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 information regarding study 445-106 for the 6 to <12 years patient group with reference to SmPC of ivacaftor/tezacaftor/elexacaftor for additional data.

5.2       Pharmacokinetic properties

Minor updates to age ranges in the paediatric population subsection, including addition of data to Table 10, related to exposures when used in combination with ivacaftor/tezacaftor/elexacaftor by age group and dose administered.

1. What Kalydeco is and what it is used for

Update to the indication statement for patients who are 6 years and older for use of Kalydeco in combination with ivacaftor/tezacaftor/elexacaftor.

2. What you need to know before you take Kalydeco

Update to header “Children and adolescents..” and safety and efficacy statement, that it is not known if Kalydeco in combination with ivacaftor/tezacaftor/elexacaftor is safe and effective in children under the age of 6 years.

       3 . How to take Kalydeco

Addition of dose recommendation table with information for the 6yrs and older age group added. The table also includes dosing information related to weight.

        6.  Contents of the pack and other information

Clarification in the manufacturer’s address that Almac Craigavon is in Northern Ireland within the United Kingdom.

Summary of changes 

• References section
• Section 4.4 Special warnings and precautions (hepatic update)
• Section 4.8 Undesirable effects (Table 4: Adverse reactions table content and footnote)
• Section 4.8 Description of selected adverse reactions (Transaminase elevations section)

Summary of changes 

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

Updated indication to align with SmPC

Section 4.1: Therapeutic indications

Updated indication to, “In a combination regimen with ivacaftor /tezacaftor /elexacaftor tablets for the treatment of adults and adolescents aged 12 years and older with cystic fibrosis (CF) who have at least one F508del mutation in the CFTR gene.”

Section 5.1: Pharmacodynamic properties- pharmacodynamic effects

Updated data for patients heterozygous for F508del mutation and a mutation on the second allel with a gating defect or residual CFTR activity

Section 5.1: Pharmacodynamic properties- clinical efficacy and safety

Updated the information to include efficacy and safety data from three phase 3 studies (not just two)

Section 5.2: Pharmacokinetic properties- Elderly

Removed a statement saying that no patients aged 65 years and older were included

Updated date

Updated date

1.    NAME OF THE MEDICINAL PRODUCT
Addition of 75 mg film-coated tablets

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Addition of 75 mg ivacaftor tablet qualitative and quantitative information.

3.    PHARMACEUTICAL FORM

Addition of pharmaceutical from information and tablet description for Kalydeco 75 mg.

4.1    Therapeutic indications

• Update to indication statement for Kalydeco used in a combination regimen with tezacaftor/ivacaftor tablets for the treatment of adults, adolescents, and children aged 6 years and older with Cystic fibrosis who are homozygous for the F508del mutation or who are heterozygous for the F508del mutation and have one of the following mutations in the CFTR gene: P67L, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272 26A→G, and 3849+10kbC→T.
• Editorial updates.

4.2    Posology and method of administration

• Some minor administrative updates throughout this section.
• Update to the dosing recommendations table to introduce information related to the 6yrs to <12 years, <30 kg and 6 years to <12 years, ≥30 kg patient groups.
• Missed dose
• Editorial updates to instructions to patients who may have missed a dose.
• Table 2 - Update to table for dosing recommendations for concomitant use with moderate or strong CYP3A inhibitors, to add information for patients using ivacaftor in a combination regimen with tezacaftor/ivacaftor (6 years to <12 years, <30 kg and 6 years <12 years, ≥30 kg).
• Table 3 - Update to table for dosing recommendations for patients with moderate or severe hepatic impairment, to add information for patients using ivacaftor in a combination regimen with tezacaftor/ivacaftor (6 years to <12 years, <30 kg and 6 years <12 years, ≥30 kg).
• Paediatric population
• Update to statement on use of Kalydeco in the paediatric population to include clarifications for patients using ivacaftor in combination with tezacaftor/ivacaftor and ivacaftor/tezacaftor/elexacaftor.

4.5    Interaction with other medicinal products and other forms of interaction

Minor editorial updates.

4.8    Undesirable effects

• Table 4 title amended.
• Paediatric population section updated to include information on peak LFT elevations being generally higher in paediatric patients than in older patients.

5.1    Pharmacodynamic properties

• In subsection “Ivacaftor in a combination regimen with tezacaftor/ivacaftor” sweat chloride data for patients aged 6 to less than 12 years who were homozygous or heterozygous for the F508del mutation and a second mutation associated with residual CFTR activity has been included.
• Paediatric population subsection updated to include summary of the study of ivacaftor in a combination regimen with tezacaftor/ivacaftor in patients aged 6 to less than 12 years.

5.2    Pharmacokinetic properties
Table 10 updated to include the ivacaftor exposure when used in combination for the 6 yrs to less than 12 years patient population.

6.5    Nature and contents of container
Administrative edits and inclusion of the pack size for Kalydeco 75 mg tablets

8.    MARKETING AUTHORISATION NUMBER(S)
Addition of marketing authorization number for 75 mg Kalydeco tablets.
 

Addition of Kalydeco 75 mg film-coated tablets

1.    What Kalydeco is and what it is used for

• Update to indication for Kalydeco tablets in combination with tezacaftor/ivacaftor tablets to include patients aged 6 years and older.

2.    What you need to know before you take Kalydeco
Children and adolescents

•     Update to clarify the age of children using Kalydeco in combination with tezacaftor/ivacaftor:
•     Do not give this medicine in combination with tezacaftor/ivacaftor to children under 6 years of age or in combination with ivacaftor/tezacaftor/elexacaftor to children under 12 years of age as it is not known if they are safe and effective for them.

3.    How to take Kalydeco

• Updated dosing recommendations table for patients who are 6 to less than 12 years <30 kg and 6 years to less than 12 years, ≥30 kg.

Use in children

 Deletion of statement regarding other forms of this medicine and their use in children under 6 years of age as not relevant in the tablets leaflet. Granules leaflet contain information for patients below 6 years of age.
    

6.    Contents of the pack and other information
Addition of 75 mg tablets and update to 150 mg tablets information.
What Kalydeco looks like and contents of the pack
Addition of Kalydeco 75 mg tablet appearance and pack size information.
 

Minor typographical change throughout the SmPC and spelling correction.

4.2          Posology and method of administration

Amended safety and efficacy statement to children less than 4 months in the Paediatric population section.

Amended method of administration to remove Seville Oranges as a food or drink to be avoided during treatment.

​​​​​​​4.5  Interaction with other medicinal products and other forms of interaction

Removal of Seville Oranges as a food or drink to be avoided during treatment when using CYP3A inhibitors.

4.8  Undesirable effects

Addition of the 6 patients between 4 months to less than 6 months of age who were studied as part of the paediatric population.

Table 5 amended to add transaminase elevations data in patients 4 months to less than 6 months of age.

Section 2. Update to “warnings and precautions” section (children and adolescents) to state that this medicine should not be given to children under 4 months of age.

Update to “Kalydeco with food and drink” to remove Seville oranges.

SmPC – Kalydeco tablets

Update to Section 2. QUALITATIVE AND QUANTITATIVE COMPOSITION

• Revised excipient with known effect text to remove “as” to “lactose monohydrate”.

Update to Section 4.1  Therapeutic indications

• Text revised to clarify Kalydeco monotherapy indication as well as Kalydeco use in combination with tezacaftor 100 mg/ivacaftor 150 mg.
• Addition of indication for Kalydeco to be used in combination with ivacaftor 75 mg, tezacaftor 50 mg, elexacaftor 100 mg.

Updated text:

In a combination regimen with ivacaftor 75 mg/tezacaftor 50 mg/elexacaftor 100 mg tablets for the treatment of adults and adolescents aged 12 years and older with cystic fibrosis (CF) who are homozygous for the F508del mutation in the CFTR gene or heterozygous for F508del in the CFTR gene with a minimal function (MF) mutation.

Updates to Section 4.2 Posology and method of administration

• Dosing recommendations table included with posology for ivacaftor as monotherapy, in combination with tezacaftor 100 mg/ivacaftor 150 mg and ivacaftor in combination with ivacaftor 75 mg/tezacaftor 50 mg/elexacaftor 100 mg

Table 1: Dosing recommendations

The morning and evening dose should be taken approximately 12 hours apart with fat-containing food (see Method of administration).

Updates to “Missed dose” section to add clarifying text around existing language and also to account for missed dose instructions where Kalydeco is used in a combination regimen.

Updated text:

Missed dose

If 6 hours or less have passed since the missed morning or evening dose, the patient should take it as soon as possible and continue on the original schedule. If more than 6 hours have passed since the time the dose is usually taken, the patient should be told to wait until the next scheduled dose.

Patients receiving ivacaftor in a combination regimen should not take more than one dose of either medicine at the same time.

Update to Concomitant use of CYP3A inhibitors section to include dosing recommendations table for ivacaftor as monotherapy, in combination with tezacaftor 100 mg/ivacaftor 150 mg and ivacaftor in combination with ivacaftor 75 mg/tezacaftor 50 mg/elexacaftor 100 mg

“Elderly” section updated to summarise language around dose adjustment

Updated text:

Elderly

Very limited data are available for elderly patients treated with ivacaftor (administered as monotherapy or in a combination regimen). No dose adjustment specific to this patient population is required (see section 5.2).

“Hepatic impairment” section updated to include the combination regimen in addition to the monotherapy. Text has been summarised and table updated.

Paediatric population

• Administrative edits and updated to include ivacaftor/tezacaftor/elexacaftor combination regimen.

Method of administration

• Information related to tablets not being chewed, crushed or broken before swallowing updated to confirm there is no clinical data to support other methods of administration, therefore tablets should be swallowed whole.

Update to Section 4.4 Special warnings and precautions for use

Minor administrative edits and references made to use of Kalydeco with combination regimens.

Hepatic impairment section updated to include information on use of ivacaftor in a combination regimen for patients with severe and moderate hepatic impairment.

Addition of text:

Hepatic impairment

Use of ivacaftor, either as monotherapy or in a combination regimen with tezacaftor/ivacaftor, is not recommended in patients with severe hepatic impairment unless the benefits are expected to outweigh the risks. Patients with severe hepatic impairment should not be treated with ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor.

For patients with moderate hepatic impairment, use of ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor is not recommended. Treatment should only be considered when there is a clear medical need and the benefits are expected to outweigh the risks. If used, it should be used with caution at a reduced dose.

Renal impairment section updated with minor edits to include information on use of ivacaftor in a combination regimen.

Patients after organ transplantation section updated with minor edits to include information on use of ivacaftor in a combination regimen.

Addition of Rash events section to SmPC

Updated text:

Rash events

The incidence of rash events with ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor was higher in females than in males, particularly in females taking hormonal contraceptives. A role for hormonal contraceptives in the occurrence of rash cannot be excluded. For patients taking hormonal contraceptives who develop rash, interrupting treatment with ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor and hormonal contraceptives should be considered. Following the resolution of rash, it should be considered if resuming ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor without hormonal contraceptives is appropriate. If rash does not recur, resumption of hormonal contraceptives can be considered (see section 4.8).

Updates to Interactions with medicinal products related to the exposure to ivacaftor and tezacaftor, elexacaftor respectively when concomitantly used with CYP3A inducers and CYP3A inihibitors, either as monotherapy or as part of a combination regimen.

Header of sub-section amended to “Paediatric population” instead of “Cataracts” and text updated to refer to ivacaftor monotherapy and as part of a combination regimen.

Update to Section 4.5 Interaction with other medicinal products and other forms of interaction

Minor administrative edits to text to reflect ivacaftor as monotherapy and combination regimens throughout this section.

Addition of “verapamil” in the example of moderate CYP3A inhibitors where a reduction in ivacaftor dose is required if concomitantly used (either when used with ivacaftor as monotherapy or as part of a combination regimen).

Subsection related to ivacaftor to interact with transporters has moved position within this section of the SmPC.

Administrative edits to section 4.6, 4.7 of SmPC

Update to Section 4.8 Undesirable effects

Update adverse events table to include additional adverse effects observed with ivacaftor in a combination regimen with either tezacaftor/ivacaftor and/or ivacaftor/tezacaftor/elexacaftor.

Footnote of table updated to differentiate  adverse effects seen in clinical studies where ivacaftor used in combination with tezacaftor/ivacaftor and/or in combination with ivacaftor/tezacaftor/elexacaftor.

Additional information related to transaminase elevations updated, in addition to new subsections related to “Rash events” and “Increased creatine phosphokinase” and “Increased blood pressure”.

Clinical studies in paediatric population section updated to include data for transaminase elevations in patients 6 months to <12 years treated with ivacaftor as monotherapy.

Updates to section 5.1 Pharmacodynamic properties

Minor administrative edits throughout section.

Addition of sweat chloride data for ivacaftor used in combination regimen with ivacaftor/elexacaftor/tezacaftor.

Addition of clinical data for two Phase 3 studies conducted in patients 12 years and older when ivacaftor was used in combination regimen with ivacaftor/tezacaftor/elexacaftor where efficacy and safety were demonstrated.

Updates to section 5.2 Pharmacokinetic properties

Minor administrative edits throughout section.

Updates to the Absorption, Distribution, Biotransformation and Elimination subsections.

Updates to special populations ( hepatic impairment and renal impairment subsections) to include information related to combination regimens.

Elderly subsection updated to clarify around PK parameters in patients over 65.

Table in Paediatric population subsection updated to include data on ivacaftor exposure when used in combination with tezacaftor and in combination with tezacaftor/elexacaftor.

Section 1. What Kalydeco is and what it is used for

• Update to PIL text to clarify indication for Kalydeco used as monotherapy and in combination regimen.

Warnings and Precautions

• Addition of ivacaftor/tezacaftor/elexacaftor combination regimen to warning related to increased liver enzymes already in the PIL
• Addition of precaution to inform your doctor if you are using hormonal contraception such as the contraceptive pill with clarification that some patients may experience rash whilst taking Kalydeco in combination with ivacaftor/tezacaftor/elexacaftor.
• Addition of ivacaftor/tezacaftor/elexacaftor combination regimen to cataracts precautions already in the PIL.
• Reformatting of “other medicines and Kalydeco” section to include medicines in alphabetical order, simplify descriptors and amend subheaders to “Antibiotic medicines” instead of antibacterial agents and Epilepsy medicines from “anticonvulsant medicines”.
• Addition of verapamil (Medicine for lowering blood pressure) to PIL

Section 3. How to take Kalydeco

• Addition of dosing recommendation table with minor text amends due to introduction of the table.

Section 4. Possible side effects

• Minor administrative edits.
• Subsection “Possible signs of liver problems” included.
• Updated side effects to also include those possibly experienced when Kalydeco is used in a combination regimen.

Minor update to Section 5.1 Pharmacodynamic properties

Reference to Completion of Study 661-110 (Study 6)

Previous text:

Kalydeco in a combination regimen with tezacaftor/ivacaftor

The efficacy and safety of Kalydeco in a combination regimen with tezacaftor/ivacaftor in patients with CF was assessed in two clinical studies; a 24 week, randomized, double‑blind, placebo‑controlled study with 504 patients aged 12 years and older who were homozygous for the F508del mutation; and a randomized, double‑blind, placebo‑controlled and ivacaftor controlled, 2 period, 3 treatment, 8‑week crossover study with 244 patients aged 12 years and older who were heterozygous for the F508del mutation and a second mutation associated with residual CFTR activity. An open‑label, rollover, 96-week study is on‑going to evaluate the long‑term safety and efficacy of the combination regimen in both patient populations. Refer to the Summary of Product Characteristics of tezacaftor/ivacaftor for additional data.

Updated text:

Kalydeco in a combination regimen with tezacaftor/ivacaftor

The efficacy and safety of Kalydeco in a combination regimen with tezacaftor/ivacaftor in patients with CF was assessed in two clinical studies; a 24 week, randomized, double‑blind, placebo‑controlled study with 504 patients aged 12 years and older who were homozygous for the F508del mutation; and a randomized, double‑blind, placebo‑controlled and ivacaftor controlled, 2 period, 3 treatment, 8‑week crossover study with 244 patients aged 12 years and older who were heterozygous for the F508del mutation and a second mutation associated with residual CFTR activity. The long-term safety and efficacy of the combination regimen was also assessed in both patient populations in a 96-week open-label, rollover, long-term extension study. Refer to the Summary of Product Characteristics of tezacaftor/ivacaftor for additional data.

• Updates associated to sections 4.1, 4.2 associated with changed to indication stating that Kalydeco tablets can be used for treatment of adults, adolescents and children aged 6 years and older who have an R117H mutation.
• Updates to sections 4.4 and 5.1 associated with the indication expansion described in section 4.1 and corresponding study data (Study 6) which has been updated/added to the SmPC.

Updates associated with use of Kalydeco in patients who are 6 years and older with R117H mutation

Previous text:

1. What Kalydeco is and what it is used for

Kalydeco contains the active ingredient ivacaftor. Ivacaftor acts at the level of the cystic fibrosis transmembrane conductance regulator (CFTR), a protein that forms a channel at the cell surface that allows the movement of particles such as chloride in and out of the cell. Due to mutations in the CFTR gene (see below), chloride movement is reduced in those with cystic fibrosis (CF). Ivacaftor helps certain abnormal CFTR proteins open more often to improve chloride movement in and out of the cell.

Kalydeco tablets are indicated for the treatment of adults, adolescents and children aged 6 years and older and weighing 25 kg or more with cystic fibrosis (CF) who have one of the following gating mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R.

Kalydeco tablets are also indicated for the treatment of adults aged 18 years and older with CF who have an R117H mutation in the CFTR gene.

Updated text:

2. What Kalydeco is and what it is used for

Kalydeco contains the active ingredient ivacaftor. Ivacaftor acts at the level of the cystic fibrosis transmembrane conductance regulator (CFTR), a protein that forms a channel at the cell surface that allows the movement of particles such as chloride in and out of the cell. Due to mutations in the CFTR gene (see below), chloride movement is reduced in those with cystic fibrosis (CF). Ivacaftor helps certain abnormal CFTR proteins open more often to improve chloride movement in and out of the cell.

Kalydeco tablets are indicated for the treatment of adults, adolescents and children aged 6 years and older and weighing 25 kg or more with cystic fibrosis (CF) who have an R117H CFTR mutation or one of the following gating mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R.

Previous text:

Children and adolescents

Do not give this medicine to children under 6 months of age with gating mutations as it is not known if ivacaftor is safe and effective in these children, or in patients under 18 years of age with an R117H mutation as ivacaftor may not work in them.

Do not give this medicine in combination with tezacaftor/ivacaftor to children under 12 years of age as it is not known if they are safe and effective for them.

Updated text:

Children and adolescents

Do not give this medicine to children under 6 months of age as it is not known if ivacaftor is safe and effective in these children.

Do not give this medicine in combination with tezacaftor/ivacaftor to children under 12 years of age as it is not known if they are safe and effective for them.

Wording in PIL updated to reflect reference to adults, adolescents and children

Section 4.1 updated wording to reflect adults, adolescents, and children rather than "Cf patients"

Section 4.2 updated wording to reflect license expansion to lower age group

Removal of black triangle.

Section 4.8: Addition of paediatric data and details of paediatric trial During the 24‑week, open‑label, Phase 3 clinical study in patients aged 12 months to less than 24 months (Study 8), the incidence of patients experiencing transaminase elevations (ALT or AST) >3, >5, and >8 x ULN was 27.8% (5/18), 11.1% (2/18) and 11.1% (2/18), respectively. No patients had elevations in total bilirubin. No patients discontinued ivacaftor treatment due to transaminase elevations. The two patients with elevations of ALT or AST >8 x ULN interrupted treatment and subsequently resumed ivacaftor successfully (see section 4.4 for management of elevated transaminases)."

Section 5.2 updates to Table 7

Section 7 MAH address change

Note inverted black triangle now removed.

Section 4.8 paediatric population data added, "The safety data of ivacaftor monotherapy were evaluated in 19 patients between 12 months to less than 24 months of age" and data on paediatric trial added "During the 24‑week, open‑label, Phase 3 clinical study in patients aged 12 months to less than 24 months (Study 8), the incidence of patients experiencing transaminase elevations (ALT or AST) >3, >5, and >8 x ULN was 27.8% (5/18), 11.1% (2/18) and 11.1% (2/18), respectively. No patients had elevations in total bilirubin. No patients discontinued ivacaftor treatment due to transaminase elevations. The two patients with elevations of ALT or AST >8 x ULN interrupted treatment and subsequently resumed ivacaftor successfully (see section 4.4 for management of elevated transaminases).

Section 5.2 Table 7 updated with new paediatric data

section 8 Marketing Authorisation Holder address changed

New wording added to sections to reflect updated SmPC

In section 3: minor editorial changes

In section 4.1: minor editorial changes

In section 4.2: minor editorial changes

In section 4.4: Removal of the warning regarding limited data in patients with FEV1 <40%. Other minor editorial changes

In section 4.5: Removal of the drug-drug interaction information for CYP2C8 substrates. Other minor editorial changes

In section 4.6: minor editorial changes

In section 4.7: minor editorial changes

In section 4.8: minor editorial changes

In section 4.9: minor editorial changes

In section 5.1: minor editorial changes

In section 5.2: minor editorial changes

In section 6.5: minor editorial changes

In section 9: minor editorial changes

Section 2: minor editorial changes
Section 4.2: minor editorial changes
Section 4.4: minor editorial changes
Section 4.5: minor editorial changes
Section 4.6: changes in relation to pre-clinical pregnancy, breast-feeding and fertility data
Section 5.1: minor editorial changes
Section 5.2: minor editorial changes
Section 5.3: changes to pre-clinical data on teratogenicity, carcinogenicity and findings of cataracts

In section 6.3 of the Tablets SmPC – the shelf life has been changed from ‘30 months’ to ‘4 years’

Changes made to Sections 4.1, 4.2, 4.4, 4.8, 5.1 and 5.2 to support introduction of a new indication for the treatment of cystic fibrosis in patients aged 18 years and older who have a R117H mutation in the CFTR gene.

Changes made to Sections 4.1, 4.2, 4.4, 4.8 and 5.2 to support revised dosing recommendations for cystic fibrosis patients aged 6 years and older and weighing 25 kg or more; as well as to align with introduction of the new Kalydeco strengths and pharmaceutical form (Kalydeco granules in sachet).

Additional editorial changes and alignment with QRD templates have been made to Sections 2, 4.5, 4.6, 4.7, 4.8, 5.3, 6.1, 6.5 and 6.6.

Vertex Pharmaceuticals (Europe) Limited

2 Kingdom Street

London W2 6BD

United Kingdom

Section 4.8, editorial changes that address the inclusion of Study 111 part 2. (Study 111 part 1 is already in the SmPC)
Section 5.1, detailed explanation of Study 111 part 2

Section 4.5: CYP3A inhibitors: Modifications to the wording in the first 2 paragraphs

Section 4.5: CYP3A inducers: Modifications to wording in first paragraph

Section 5.2: Distribution: Deletion of the sentence, “The apparent volume of distribution (Vz/F) of ivacaftor after a single dose of 275 mg in the fed state was similar for healthy subjects and patients with CF.”

Section 5.2: Elimination: change “the 150 md dose” to a single 150 mg dose, and delete the words, “at steady state”

Section 5.2: Paediatric population: Replaced entire paragraph, and added Table 6 just under the new paragraph. New paragraph states:

Non-compartmental analysis of sparse PK samples collected in Phase 3 studies demonstrate an apparent (oral) clearance (CL/F) that was lower in children than in adults and resulted in approximately 47% to 58% higher AUC_0-12  and 35% to 46% higher C_trough in children 6 to <12 years old relative to adults (Table 6). Due to sparse PK sampling ivacaftor volume of distribution and half-life cannot be calculated.

Overview: Addition of Study 4 (open-label extension study) and associated changes to ADRs in Tables 1 and 2, and addition of new Table 4; and Study 5 (study in patients with non-G551D gating mutations): Extension of Indication to include additional gating (class III) mutations in the CFTR gene: G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N and S549R and associated data.

Section 4.1 (therapeutic indications): added new class III gating mutations; indicated mutations are G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, and S549R

Section 4.2 (posology and method of administration) Updated to note that genotyping should be performed to confirm the presence of one of the indicated class III mutations

Section 4.4: (special warnings and precautions for use) Added information for Study 5

Section 4.8 (undesirable effects):

·        updated summary of the safety profile to include study 5;

·        updated Table 1: changed AR frequency status of dizziness, vestibular disorder, and breast mass; changed N’s to cover study 5

·        updated Table 2: changed AR frequency status of dizziness, diarrhea, and investigations; added tinnitus, sinus congestion, and breast mass as new ARs based on new study 5 data; changed N’s to cover Study 5

Section 5.1 (pharmacodynamics properties):

·        reworded the Mechanism of action description;

·        added efficacy data from Study 5 including new Table 4; added description of Study 5

·        changed description of Study 4 and added new Table 5 to cover efficacy from open-label extension study

Section 5.2 (pharmacokinetic properties): deleted paragraph on pharmacokinetic/pharmacodynamic relationships; changed Paediatric population paragraphs to cover Study 5 PK parameters in this population

New text shown in red, deleted text shown by strikethrough

Section 4.2: Concomitant use of CYP3A inhibitors:
When co-administered with potent strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin and clarithromycin), Kalydeco should be administered at a dose of 150 mg twice a week (see sections 4.4 and 4.5).

Section 4.4: Interactions with medicinal products:
Ivacaftor is a substrate of CYP3A4 and CYP3A5 isoenzymes. Medicinal products that inhibit or induce CYP3A activity, may impact the pharmacokinetics of ivacaftor (see section 4.5). The dose of Kalydeco must be adjusted when concomitantly used with strong or moderate CYP3A inhibitors. Exposure to ivacaftor may be reduced by the concomitant use of CYP3A inducers, potentially resulting in loss of Kalydeco efficacy (see sections 4.2 and 4.5).

Ivacaftor is a weak CYP3A inhibitor and may modify the pharmacokinetics of medicinal products metabolised through the CYP3A system. In vitro studies indicated that ivacaftor has the potential to inhibit P-glycoprotein (P-gp) and CYP2C9. Ivacaftor is a weak inhibitor of P-glycoprotein (P-gp) and may increase the exposure of medicinal products that are substrates for P-gp The dose of Kalydeco must be adjusted when concomitantly used with potent and moderate CYP3A inhibitors. Exposure to ivacaftor is reduced by the concomitant use of CYP3A inducers, therefore potentiallyl resulting in loss of efficacy of Kalydeco (see sections 4.2 and 4.5).

Section 4.5: Interaction with other medicinal products and other forms of interaction
Ivacaftor is a substrate of CYP3A4 and CYP3A5. It is a weak inhibitor of CYP3A and P-gp and a potential inhibitor of P-gp and CYP2C9.

Section 4.5: CYP3A, P-gp or CYP2C9 substrates
Based on in vitro results, iIvacaftor and its M1 metabolite have the potential to inhibit CYP3A and P-gp. Co-administration with (oral) midazolam, a sensitive CYP3A substrate, increased midazolam exposure 1.5-fold, consistent with weak inhibition of CYP3A by ivacaftor. Co-administration with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold, consistent with weak inhibition of P-gp by ivacaftor.

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 to the IMB (see www.imb.ie or e-mail imbpharmacovigilance@imb.ie).